Research progress on mesenchymal stem cell‑derived exosomes in the treatment of osteoporosis induced by knee osteoarthritis (Review)
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- Published online on: July 30, 2025 https://doi.org/10.3892/ijmm.2025.5601
- Article Number: 160
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Copyright: © Xue et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Knee osteoarthritis (KOA) is a prevalent degenerative joint disease characterized by progressive cartilage degeneration, synovial inflammation, and periarticular bone remodeling (1). It is a leading cause of pain and disability in elderly individuals. In 2021, KOA caused 30.85 million incident cases, 374.74 million prevalent cases, and 12.02 million disability-adjusted life years (DALYs) worldwide, with age-standardized rates (ASRs) of 353.67, 4294.27 and 137.59, respectively. Female patients and individuals aged >50 years are high-risk groups, and regions with higher sociodemographic indices are high-risk areas. From 1990 to 2021, incident cases increased from 14.13 to 30.85 million, prevalent cases from 159.80 to 374.74 million, and DALYs from 5.15 to 12.02 million, with corresponding ASR increases (2). In China (2021), the number of patients with KOA has reached 10,957,472, a 157.15% increase since 1992. The incidence was 8,512,396, a 123.45% increase from 1992. Disability rates reached 249.81 per 100,000 people, 116.44% higher than in 1992. KOA incidence increased with age in 2021 (3). Although not directly causing mortality, KOA significantly reduces life expectancy and quality of life, imposing substantial economic burdens.
Osteoporosis (OP), a metabolic bone disorder characterized by reduced bone mass and deteriorated microarchitecture (4), also severely impairs patients' quality of life (5). Both OP and osteoarthritis (OA) are prevalent age-related degenerative orthopedic disorders with strong pathophysiological links (6). China's aging population has increased the prevalence of these disorders, significantly compromising elderly patients' quality of life. Research has confirmed that OP is a risk factor for OA (7), with bidirectional pathological interactions between these conditions (7,8). Elderly patients with OP frequently develop concurrent KOA (9), which is associated with high comorbidity rates. OP significantly increases KOA risk (10), and these conditions mutually exacerbate disease progression (10). In Japan, 62.7% of individuals ≥60 years of age have both KOA and OP vs. single-disease presentations (11). This comorbidity rate increases with age, especially in women (11). A 2025 multicenter study (KOA-OP Global Consortium) of 32,000 patients with KOA across 15 countries reported an OP prevalence of 20-35% in patients KOA vs. 12-18% in non-KOA controls (12). In regions such as China and Japan, low body mass index (BMI; <23 kg/m2) and vitamin D deficiency contribute to OP incidence rates ranging from 28-35% (13). Postmenopausal women with KOA have twice the OP incidence of men (15%); estrogen decline combined with inflammatory factors (IL-6, TNF-α) accelerates bone loss (8). The prevalence of OP is greater in obese patients with KOA, but the OP incidence is lower (18-25%), which is potentially linked to variations in calcium intake and exercise (14). The epidemiological and pathological relationships between KOA and OP are clinically complex and extend beyond mutual exclusivity. Multiple studies have reported comorbidity rates ranging from 8-30% in specific populations (Table I) (15-21). Clinically, moving beyond the misconception that 'OA protects against OP' is crucial, especially for slender elderly women requiring emphasis on bone health. Future studies should integrate radiomics, genomics and multidimensional data to develop risk prediction models and personalized management strategies for this population. Notably, anti-OP therapies such as bisphosphonates effectively manage KOA and delay progression (5,22). Preoperative anti-OP treatment improves recovery and prognosis in patients with KOA receiving total knee arthroplasty (23). Traditional KOA and OP therapies face significant challenges. Pharmacological therapies incur substantial side effects, physical interventions show limited efficacy, and surgeries carry inherent risks with prolonged recovery (Table II) (24-26). Mesenchymal stem cell-derived exosomes (MSC-Exos) have revolutionized KOA/OP treatment via unique multitarget mechanisms (27,28). These nanovesicles deliver diverse bioactive molecules that precisely modulate the osteoarticular microenvironment (29). Compared with conventional therapies, MSC-Exos show superior safety, efficacy and durability (27).
Exosomes (30-200 nm in diameter) are extracellular vesicles (EVs) secreted by diverse cell types, including mesenchymal stem cells (MSCs), endothelial cells and fibroblasts. These lipid bilayer vesicles encapsulate bioactive molecules [lipids, proteins, DNA and microRNAs (miRNAs or miRs)] that are released into tissue fluids. Within the bone microenvironment, exosomes regulate bone cell proliferation and differentiation, indicating their therapeutic potential for OP (30,31). They stimulate bone regeneration mechanisms through the modulation of osteogenesis and angiogenesis. Their effects involve two mechanisms: i) facilitating intercellular communication by signaling mediators (32) and ii) performing physiological functions that support bone repair/regeneration (Fig. 1). They modulate bone cell physiology and pathology, maintaining bone homeostasis (33). However, osteoclast-derived exosomes downregulate type I collagen expression, promoting osteoclastogenesis while inhibiting osteoblast differentiation. This promotes extracellular matrix degradation and bone loss, accelerating OP progression (31). Recently, MSC-derived exosomes have gained significant attention for their unique tissue-repair functions, particularly in KOA and OP treatment (34,35). The present review examines advances in MSC-exosome applications for KOA and OP treatment and their therapeutic mechanisms.
Emerging status of MSC-Exos in disease therapy
Recently, MSC-derived exosomes have emerged as crucial mediators of intercellular communication, attracting substantial research attention (36). These exosomes carry rich biological information and demonstrate multiple bioactivities, such as anti-inflammatory, immunomodulatory, and tissue repair-promoting effects (37-39). Through target cell interactions, they play critical roles in treating various diseases, especially KOA and OP. Studies have demonstrated that MSC-derived exosomes alleviate inflammation, stimulate regeneration, regulate bone metabolism, and enhance joint function (34,35,40).
Overview of MSC-Exos
Origin and characteristics of MSCs
Different sources of MSCs (bone marrow, fat)
MSCs are multipotent cells with diverse sources (Fig. 2) that are capable of differentiating into osteoblasts, chondrocytes and adipocytes. Among the earliest identified subtypes (41), bone marrow-derived MSCs (BM-MSCs) exhibit potent self-renewal and multilineage differentiation, enabling broad clinical applications in tissue repair and regeneration (42). Adipose tissue provides another major MSC source in addition to bone marrow (43,44). Compared with BM-MSCs, adipose-derived MSCs (AD-MSCs) show comparable proliferation and differentiation potential, with greater accessibility (45). MSCs can also be isolated from the umbilical cord, placenta and dental pulp. Each MSC source (Fig. 2) provides distinct clinical advantages (46). However, despite variations in molecular profiles, proliferation rates, and immunogenicity across sources, all MSCs retain high multilineage differentiation potential and can be induced into specific cell types (47).
Self-renewal and multidirectional differentiation potential of stem cells
Stem cell self-renewal enables prolonged survival through continuous division and the production of new stem cells (48). This capacity underpins MSC applications in regenerative medicine (48). MSCs exhibit robust multilineage differentiation potential (49), enabling their ability to differentiate into osteoblasts, chondrocytes, adipocytes and neurons under specific induction conditions (49). This multipotency highlights the therapeutic value of MSCs for tissue repair and regeneration (50). Previous studies have confirmed the clinical efficacy of MSCs in bone and joint repair, immunomodulation, and other areas, suggesting broad therapeutic applications (51,52).
Formation, structure and composition of exosomes
Biogenesis of exosomes
Exosomes (30-150 nm in diameter) function as carriers for intracellular biomolecules, including proteins, lipids and RNA (53). Their biogenesis mainly occurs via the endocytic pathway (54). During endocytosis, early endosomes form from the plasma membrane and mature into late endosomes. These mature into multivesicular bodies (MVBs) that migrate toward the plasma membrane. MVBs fuse with the plasma membrane, releasing vesicular contents as exosomes extracellularly. Exosome generation involves not only endocytosis but also membrane vesicle formation and remodeling dynamics (54,55). Exosomal cargo derives from the cytoplasm, plasma membrane, and intracellular compartments, reflecting the physiological state and biological features of parent cells (56). The distinct formation mechanisms and biological significance of each extracellular vesicle biogenesis stage are summarized in Table III (57-59).
 | Table IIIMechanisms and biological significance of the various stages of extracellular vesicle biogenesis. |
Nucleic acids (miRNAs and mRNAs), proteins and other components in exosomes
Exosomes contain diverse bioactive molecules-primarily nucleic acids and proteins-that enable functional versatility (Fig. 2) (40). Exosomal nucleic acids [miRNAs, mRNAs and long non-coding RNAs (lncRNAs)] mediate intercellular communication and regulate gene expression (40). miRNAs bind target mRNAs to suppress expression and modulate cellular processes (60). mRNAs encode genetic information for protein synthesis in recipient cells. Exosomal proteins participate in cell-cell communication, membrane remodeling and immunoregulation (60). This cargo includes receptors, enzymes and transporters that modulate recipient cell functions and facilitate intercellular communication (60). In Table IV (61-74), it is reported that MSC-Exos (regardless of their miRNA/lncRNA content) increase osteoblast differentiation, regulate immunity, and ameliorate KOA-related and primary OP (75).
Mechanisms of MSC-Exos in tissue repair
Intercellular communication
MSC-Exos serve as pivotal intercellular mediators and function as signaling vehicles transporting miRNAs, mRNAs and proteins to regulate target cell activities (76). This process is essential for tissue repair and regeneration. Upon tissue injury, MSCs secrete exosomes that deliver repair signals to adjacent cells in damaged regions. Exosomal bioactive molecules (for example, miRNAs) modulate target cell gene expression via receptor interactions, thereby promoting proliferation, migration and differentiation to accelerate tissue repair (77). In bone injury repair (for example, OP), MSC-Exos critically regulate osteoclast/osteoblast activity to maintain the metabolic balance of bone. This coordinated action enhances bone repair/regeneration, demonstrating therapeutic potential for regenerative medicine (78).
Influence on immune regulation
Previous studies have highlighted the immunomodulatory effects of MSC-Exos. MSC-Exos demonstrate potent immunosuppressive properties, regulating immune responses via multiple pathways (79). These exosomes modulate immune cells (for example, dendritic cells, T cells and B cells), suppressing excessive inflammation and mitigating tissue damage (80). MSC-Exos inhibit T-cell activation by modulating dendritic cell function, attenuating downstream immune responses (81). They regulate T-cell differentiation by suppressing proinflammatory Th17 cells and promoting regulatory T cells (Tregs), effectively inhibiting immune hyperactivation (82). This immunoregulatory capacity is critical for managing OP and arthritis. By suppressing local immune hyperactivation, they minimize tissue damage and promote repair/regeneration (83). They modulate macrophage polarization toward anti-inflammatory phenotypes, alleviating local inflammation (Table V) (84-88).
Signaling pathways that promote tissue regeneration
MSC-Exos modulate multiple signaling pathways to promote tissue regeneration/repair (89). These exosomes activate signaling cascades to increase cell proliferation, differentiation and migration (90-92). Specifically, MSC-Exos utilize the Wnt/β-catenin pathway for tissue repair/regeneration (93). Exosomal miRNAs activate Wnt/β-catenin by targeting pathway genes, promoting osteoblast/chondrocyte differentiation and enhancing bone and joint repair (94). MSC-Exos also modulate the TGF-β, Notch, and PI3K/AKT pathways to regulate cellular functions and promote regeneration (95-97). The TGF-β pathway critically regulates cartilage repair and bone remodeling (95). By modulating this pathway, they enhance cartilage matrix synthesis and suppress degradation (98). Similarly, MSC-Exos regulate the Notch pathway to stimulate angiogenesis and cell differentiation, promoting vascular endothelial proliferation/migration and providing a nutrient supply for repair (99).
Pathophysiology of KOA and OP
Pathological changes associated with KOA
Articular cartilage degeneration
Articular cartilage primarily consists of hyaline cartilage. It cushions joint pressure, minimizes friction, and protects joint surfaces (100). Age, trauma, or overuse causes progressive chondrocyte dysfunction, leading to cartilage degeneration and destruction (101). Smooth surfaces and even synovial fluid distribution in healthy cartilage are demonstrated in Fig. 3; however, in KOA, cartilage becomes thinner, fragmented and worn, exposing subchondral bone (102). This degradation exacerbates joint instability and dysfunction, impairing mobility and causing pain and swelling. Cartilage degeneration involves the breakdown of the extracellular matrix, including the loss of collagen and glycosaminoglycan (for example, hyaluronic acid), which impairs mechanical stress resistance (103). Imbalanced matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) further accelerate matrix degradation, exacerbating cartilage damage (104). Degenerated cartilage lacks self-repair capacity and structural stability, which results in uneven joint surfaces, restricted mobility, and reduced quality of life due to persistent pain/swelling (105).
Synovial inflammation
The synovial membrane lines the joint cavity and is crucial for the secretion of synovial fluid, which lubricates joints and enables smooth movement (106). In KOA, pathological changes primarily involve synovial inflammation (107). Under normal conditions, the synovium maintains joint lubrication and nutrient supply; however, in KOA, inflammation induces synovial thickening, fluid exudation, and inflammatory mediator production (108). Immune cells (for example, macrophages, T cells and B cells) infiltrating the synovium propagate local inflammation and trigger the release of proinflammatory cytokines, including interleukins and TNF-α (109). These cytokines not only exacerbate synovial inflammation but also promote cartilage degradation and bone resorption through osteoclast activation in articular tissues (109). Synovial inflammation frequently coincides with intra-articular exudate accumulation, causing joint swelling and pain (108). Chronic inflammation may cause synovial fibrosis, thereby restrict joint mobility and increasing the degree of injury risk (108).
Bone changes around the joints
Articular cartilage deterioration and persistent synovial inflammation expose bone tissue to abnormal mechanical stress and inflammatory mediators, inducing structural bone alterations (110). In knee joint OP, compromised bone structure and weakened trabeculae with progressive OP severity substantially diminish bone mechanical strength (111). This impairs bone load-bearing capacity and elevates fracture risk (114). Periarticular osteophytes (bone spurs) represent another characteristic pathological feature of KOA (112). Osteophytes develop through local bone hyperplasia triggered by cartilage wear, compensating for cartilage loss (112). Despite this compensatory function, osteophytes often correlate with joint dysfunction and chronic inflammation (113). These changes further restrict joint mobility, causing pain and motor impairment (113). Research has underscored the pivotal role of periarticular bone changes in KOA progression, demonstrating that damage extends beyond cartilage, which directly compromises bone health and function (113), as shown in Fig. 4.
Pathological characteristics of OP
Mechanism of bone loss (imbalance between osteoclasts and osteoblasts)
OP is a metabolic disorder featuring reduced bone mass and deteriorated microarchitecture (4). The core mechanism of bone loss involves an imbalance between osteoclast-mediated resorption and osteoblast-driven formation (114). Normally, bone remodeling maintains the dynamic equilibrium between these processes through tight regulation (84). In OP, however, elevated osteoclast activity accelerates resorption, whereas diminished osteoblast activity impairs bone formation (114). Osteoclast overactivation frequently results from the upregulation of resorption factors such as receptor activator of nuclear factor-kappaB ligand (RANKL) and TNF-α (115). These factors promote osteoclast differentiation and activation, thereby exacerbating bone loss. Moreover, suppressed bone formation pathways (for example, Wnt/β-catenin) reduce osteoblast function and impair bone formation (116). This imbalance causes progressive bone mineral density loss, microarchitectural damage, and elevated fracture risk (117).
Fracture of bone microstructure
In OP, the bone microstructure-especially the trabecular bone arrangement and density-is significantly impaired (118). Normal trabeculae exhibit a highly organized network structure that confers mechanical strength and stability. Conversely, OP bone shows trabecular thinning and fragmentation, critically compromising its load-bearing capacity (119). Trabecular thinning and breakage directly impair structural integrity, substantially increasing fracture risk (119). Microstructural damage further modifies bone biomechanical properties (119). Trabecular loss reduces bone elasticity and toughness, increasing fracture susceptibility under stress (118). This microarchitectural destruction also correlates with reduced bone retention/regeneration capacity, impairing self-repair and exacerbating disease progression (118), as summarized in Table VI (120-123).
Changes in hormones and factors related to abnormal bone metabolism
OP development closely correlates with hormonal fluctuations and regulatory factor alterations (124). The most significant change involves estrogen decline, especially postmenopause, establishing estrogen deficiency as a primary OP driver (124). Estrogen critically regulates bone metabolism through the inhibition of osteoclast activity (124). A reduction in estrogen increases osteoclast activity, thereby increasing bone resorption and causing bone mass loss (124). In addition to estrogen, hormones, including parathyroid hormone (PTH), calcitonin, and insulin-like growth factor (IGF), significantly modulate bone metabolism (125-127). Excessive PTH secretion directly activates osteoclasts, accelerating bone loss (125). Conversely, calcitonin inhibits bone resorption, and calcitonin deficiency may accelerate OP progression (127).
Mutual relationship between the two
Sharing of inflammatory mediators
The pathological interplay between KOA and OP is strongly linked to inflammatory mediators and pathways (Fig. 5), which constitute central mechanisms connecting these conditions (128). There is significant overlap between local and systemic inflammatory responses in KOA and OP (129). In KOA, synovial inflammation triggers the release of proinflammatory cytokines (TNF-α, IL-1 and IL-6), which not only accelerate articular cartilage degradation but also promote OP development via systemic circulation (130). Inflammatory factors stimulate osteoclast activity, accelerating bone resorption and reducing bone density (131). In patients with KOA, persistently elevated inflammatory factors may critically drive OP progression (132). Similarly, aberrant bone metabolism in OP amplifies OA-associated inflammatory responses (133). Enhanced osteoclast activity in OP causes the release of proinflammatory factors into the joint fluid, inducing or exacerbating joint inflammation (133). Shared inflammatory mediators create a vicious cycle that exacerbates pathological progression in both disorders (137). Cartilage degeneration primarily features degradation of the extracellular matrix (composed mainly of type II collagen and proteoglycans) and suppression of chondrocyte function (134). Inflammatory cytokines accelerate this process by activating multiple enzymes and signaling pathways. Inflammatory cells (for example, macrophages and synovial fibroblasts) release TNF-α and IL-1β, which upregulate the activity of MMPs, particularly MMP-1, MMP-3 and MMP-13 (Fig. 5). These enzymes directly degrade collagen fibers and proteoglycans, destroying the cartilage structure (135). In OA, IL-1β enhances MMP expression via NF-κB signaling, causing cartilage elasticity loss (MMP-13 overexpression increases cartilage degradation by >40%) (136). Moreover, inflammation inhibits TIMPs, disrupting the balance between matrix degradation and synthesis (137). TNF-α and IL-6 suppress type II collagen and proteoglycan gene transcription via JAK-STAT signaling while promoting production of reactive oxygen species (ROS), inducing oxidative stress (138). This subsequently triggers chondrocyte apoptosis and senescence and reduces the self-repair capacity of the extracellular matrix (138). In rheumatoid arthritis, synovial inflammation infiltrates cartilage boundaries and directly induces cell death via the Fas ligand pathway (inflammatory environments reduce chondrocyte viability by 30%) (139). Proinflammatory cytokines (IL-1, IL-6 and TNF-α) stimulate osteoblasts and immune cells to release RANKL. RANKL binds to the receptor RANK on osteoclast precursors, activating the NF-κB and NFATc1 signaling pathways to induce osteoclast differentiation and maturation (140).
Common influence of mechanical factors on both
Mechanical factors play a pivotal role in the KOA-OP interplay (Fig. 5) (141,142). KOA typically involves increased joint loading and irregular motion, generating abnormal mechanical stress that accelerates articular cartilage degeneration (143). In patients with KOA, such mechanical stresses exacerbate joint wear, increase bone pressure, and promote bone loss, thereby intensifying OP (144). Conversely, OP reduces bone load-bearing capacity, increasing fracture susceptibility under excessive mechanical stress. Progressive KOA induces joint imbalance and aggravated OP, creating a cycle where mechanical factors continuously compound stress on knee joints and bones, worsening both conditions (141).
Common cellular and molecular mechanisms
In addition to mechanical factors, KOA and OP share cellular and molecular mechanisms, notably in inflammatory and bone remodeling pathways (145). Osteoclast activation represents a critical commonality in both pathologies (146). In KOA, inflammatory mediators stimulate osteoclast activation (Fig. 6), enhancing bone resorption and exacerbating joint damage (147). Similarly, osteoclast overactivity in OP causes substantial bone loss (148). Additional shared mechanisms include osteoblast inhibition and reduced bone formation, which accelerate disease progression (149). The RANKL-RANK-OPG axis is central to both conditions at the molecular level (150). Elevated RANKL promotes osteoclast activation, whereas reduced osteoprotegerin (OPG) fails to counteract this effect, and this imbalance causes excessive bone resorption and structural degradation (Fig. 6) (150). Thus, RANKL/OPG imbalance constitutes a key molecular mechanism linking KOA and OP pathogenesis.
Mechanisms specific to the KOA microenvironment for bone microstructural destruction
KOA is characterized by articular cartilage degeneration, bone destruction and osteophyte formation. Articular cartilage comprises chondrocytes, collagen fibers, and a gel-like extracellular matrix (151). As shown in Table VII (152,153), there are significant differences in the characteristics between KOA cartilage and healthy cartilage. Various factors disrupt intra-articular homeostasis, particularly during mechanical loading. Increased surface friction in cartilage induces compensatory subchondral bone plate hyperplasia. Electron microscopy reveals brush-textured cartilage surfaces with increased roughness (154). OP manifests as reduced bone mass, microarchitectural deterioration, and increased skeletal fragility (155). Osteoporotic bone sections exhibit cortical thinning with irregular bone and cartilage surfaces (156). Age-related subchondral OP causes cortical degeneration, resulting in uneven articular cartilage stress distribution. Consequently, trabecular destruction, articular surface collapse and irreversible bone damage contribute to KOA pathogenesis (157). Mechanical instability and stress imbalance disrupt knee joint homeostasis, promoting KOA development. Concurrently, decreased sex hormone secretion and impaired mineral absorption (calcium, phosphorus) contribute to OP (158). During KOA pathogenesis, synovial macrophages and chondrocytes release IL-1β, TNF-α and IL-6, activating NF-κB signaling. These pathways suppress osteoblast function while promoting osteoclast differentiation via RANKL/RANK/OPG signaling (159). This causes bone remodeling imbalance, enhanced osteoclastic resorption and reduced osteoblastic formation, leading to subchondral microstructural damage, including microporosity and trabecular fractures (159). In KOA (vs. OP), Wnt/β-catenin signaling is hyperactivated, promoting bone sclerosis and inhibiting cartilage repair (160). Concurrently, Gli-mediated Hedgehog signaling upregulation induces osteophyte formation and vascular invasion, disrupting hypoxic homeostasis in bone (161). Post-trauma or mechanical wear, chondrocytes and synoviocytes release IL-1β (interleukin-1β), TNF-α (tumor necrosis factor-α) and PGE2 (prostaglandin E2), stimulating osteoclast secretion of MMPs and TIMPs. Consequently, the cartilage ECM degrades, bone regeneration is impaired, and irreversible tissue degeneration/apoptosis occurs (162). Synovial fluid exosomal miRNAs (for example, miR-140-5p and miR-29b-3p) regulate osteogenesis by suppressing Runx2 and activating osteoclastogenic transcription factors such as NFATc1 (163). In OP, RANK (nuclear factor-κB)-RANKL binding promotes osteoclast differentiation/maturation, enhances resorption, and inhibits apoptosis (164). Upregulated RANK transcription with concurrent OPG downregulation reduces osteoblastogenesis, causing bone loss in OP (164). Single-cell RNA sequencing has revealed >50% downregulation of Wnt target genes in patients with OP (165). Consequently, Wnt ligand (for example, Wnt3a, Wnt10b)-receptor (LRP5/6, Frizzled) binding decreases, β-catenin degradation complex (APC/Axin/GSK-3β) inhibition decreases, and β-catenin nuclear translocation decreases, impairing TCF/LEF activation. This cascade reduces osteogenic gene expression, impairs osteoblastogenesis, and exacerbates osteoporotic bone loss.
Combined effects of genetic predisposition and environmental factors on the development or progression of OA-associated OP
The relationship between OA and OP is complex and remains a central focus in skeletal research. Gene-environment interactions critically drive OA-associated OP development (164,166,167). Genome-wide association studies identify OA/OP-associated loci, including COL1A1, VDR and LRP5. These genes regulate bone metabolism, cartilage formation and inflammatory responses (168). TNFRSF11B variants disrupt RANKL/OPG signaling, increasing bone turnover by ≤50% (169). Bone metabolism-related genes, such as the VDR FokI polymorphism, reduce intestinal calcium absorption by 30-40%, lowering bone mineral density (170). COL2A1 mutations cause type II collagen defects, accelerating cartilage matrix degradation. Epidemiological studies indicate that carriers have a 2.3-fold greater risk of OA (171). Environmental factors epigenetically regulate gene expression in OA-OP pathogenesis (172). Nutritional status, mechanical loading, and inflammatory microenvironments induce epigenetic changes (DNA methylation, histone modifications) (173). Intrauterine nutritional restriction induces FTO methylation changes, causing offspring adipokine dysregulation and a pro-inflammatory microenvironment (174). Mechanical loading critically links OA and OP pathogenesis (175). Aberrant mechanical loading disrupts bone remodeling through the Wnt/β-catenin and RANKL/OPG pathways (176). Obesity (BMI >30) quadruples synovial leptin secretion vs. normal, directly activating chondrocyte apoptosis (177). The genetic background determines mechanical sensitivity variation (178). GDF5 variants cause mechanotransduction defects, increasing OA-OP susceptibility under mechanical stress (179). RUNX2 risk alleles blunt the osteogenic response to low-intensity activity (<3 METs): the level of bone alkaline phosphatase (ALP) increases by only 15% vs. 40% in the wild type (180). Adolescent calcium deficiency (<800 mg/day) with LRP5 variants causes ≤12% peak bone mass deficit, which is exacerbated postmenopause (181). Understanding gene-environment interactions enables the following: i) early high-risk genotype screening, ii) genetically tailored nutrition strategies, and iii) personalized mechanical loading regimens.
Mechanism of MSC-Exos in the treatment of KOA
Repair effect of articular cartilage
Promotion of chondrocyte proliferation
MSC-derived exosomes show significant reparative potential for OA treatment, primarily by promoting chondrocyte proliferation and regeneration [Table VIII; (95,182-191)]. Cartilage degeneration with chondrocyte damage is a hallmark of KOA (192). Chondrocytes have limited proliferative capacity; their age/disease-dependent depletion severely impairs cartilage repair (193). MSC-derived exosomes enhance chondrocyte proliferation and function via multiple mechanisms (194). These exosomes contain growth factors, cytokines and miRNAs (195) that bind chondrocyte receptors to activate downstream signaling. TGF-β, IGF-1 and bFGF stimulate chondrocyte proliferation/differentiation to promote cartilage repair (195). These factors also increase chondrocyte survival, reduce apoptosis, and promote regeneration (196). MSC-derived exosomes reduce TNF-α/IL-1β-induced chondrocyte apoptosis by 40-60% (annexin V/PI staining) and increase proliferation by 30-50% (197,198). In a rat OA model, intra-articular extracellular vesicle injection reduced the number of TUNEL+ cells >50% at 2 weeks (198). Chondrocyte density increases 25-40%, with improved OARSI scores after 4 weeks of treatment (199).
Regulating cartilage matrix synthesis and catabolism
Articular cartilage degeneration in KOA primarily results from cartilage matrix destruction, which is characterized by the loss of essential components, including collagen fibers and proteoglycans (104). Cartilage injury is fundamentally driven by imbalances in cartilage matrix metabolism (104). MSC-derived exosomes critically regulate cartilage matrix synthesis and catabolism (200). These exosomes modulate the cartilage matrix synthesis-degradation equilibrium through multiple mechanisms, delaying articular cartilage degeneration (200). Through containing growth factors and cytokines, these exosomes enhance matrix synthesis (201). Exosomal TGF-β and IGF-1 activate cartilage matrix production genes, enhancing the synthesis of critical components, including type II collagen and proteoglycans. This process enhances cartilage structural integrity and functionality (202,203). In addition to promoting matrix synthesis, exosomal miRNAs facilitate cartilage repair through the regulation of cartilage matrix production genes (200). MSC-derived exosomes also suppress cartilage matrix catabolism (200). In KOA, elevated osteoclast activity accelerates cartilage matrix breakdown, driving progressive cartilage loss (204). Exosomal components (for example, miRNAs and anti-inflammatory factors) inhibit MMPs-key cartilage-degrading enzymes-thereby reducing breakdown rates (205). MMP overactivation, as a key driver of cartilage matrix degradation, is fundamentally linked to cartilage degeneration.
Inhibition of synovial inflammation
Reduced release of inflammatory factors
Synovial inflammation-a key pathological feature of KOA-manifests as inflammatory cell infiltration and mediator release within the synovium (Fig. 6) (206). This response exacerbates joint damage, causing cartilage degradation and functional impairment; moreover, proteins, genetics, hormones, and biomechanics contribute to KOA and OP pathogenesis (207). MSC-derived exosomes attenuate synovial inflammation via multiple pathways (Fig. 5), suppressing proinflammatory factor release and decelerating KOA progression (Figs. 5 and 7) (208,209). These exosomes contain abundant anti-inflammatory molecules, including cytokines and chemokine inhibitors (208). Exosomal anti-inflammatory components (for example, TGF-β and IL-10) suppress synovial cell release of mediators (IL-1β, TNF-α and IL-6), thereby attenuating inflammation (Fig. 8) (93). IL-10 and TGF-β demonstrate potent immunoregulatory effects: they inhibit proinflammatory immune cells (for example, Th1 and Th17 cells) while promoting anti-inflammatory cell expansion. This immunomodulation significantly reduces synovial inflammation (210). Sphingosine-1-phosphate (S1P) binds S1PR1, activating the PI3K/Akt pathway to i) promote IL-4/IL-13 secretion and ii) inhibit macrophage M1 polarization (211). 15d-PGJ2 (prostaglandin J2) functions as a PPARγ ligand, inhibiting iNOS/COX-2 expression and reducing NO/PGE2 production (212).
Regulating synovial cell function
Pathological changes in KOA-particularly synovial cell dysfunction and cartilage degeneration-exacerbate disease progression (213). MSC-Exos critically regulate synovial cell function, preventing pathological activation and ameliorating KOA symptoms (214). These exosomes suppress synovial cell proliferation and migration, thereby reducing synovial hypertrophy and cartilage erosion (215). Excessive proliferation and aberrant migration of synovial cells constitute pivotal drivers of KOA progression (216). In vivo studies have demonstrated that MSC-exosomal anti-inflammatory factors/miRNAs regulate synovial cell cycle progression, curtailing hyperplasia and delaying synovial hypertrophy (217). Furthermore, MSC-Exos modulate synovial secretory function, decreasing the levels of cartilage-damaging inflammatory factors/enzymes (218). During inflammation, synovial cells overexpress proinflammatory cytokines and matrix metalloproteinases, aggravating cartilage injury (219). MSC-Exos regulate the expression of these mediators, suppressing inflammation and limiting cartilage degradation. Collectively, this regulation enhances joint function and structural integrity, suggesting therapeutic potential for KOA management.
Outline of possible protective mechanisms of OP
Decreased bone resorption
Regulated activation and proliferation of osteoclasts
MSC-Exos regulate osteoclast function in KOA-associated OP (220). KOA is characterized by chronic inflammation and abnormal mechanical stress, promoting osteoclast proliferation/activation and enhancing bone resorption (221). MSC-exosomes modulate osteoclast metabolism and differentiation signaling pathways, ameliorating OP pathology (222). In KOA-associated OP, TNF-α/IL-6 enhances osteoclast activity via the NF-κB/MAPK signaling pathways (223). Through bioactive components (miRNAs/lncRNAs/proteins), MSC-Exos regulate these pathways, inhibiting osteoclastogenesis. MSC-exosomal miR-141-3p targets TRAF5/TRAF6, inhibiting NF-κB signaling to i) decrease RANKL expression, ii) suppress osteoclast activation, and iii) reduce bone resorption (224,225). Osteoblasts exhibited morphological improvements, increased actin microfilaments, and a larger cell area 5 days after transfection with the miR-141-3p mimic (226). Additionally, MSC-exosomes mitigate oxidative stress by reducing accumulation of ROS (227). Consequently, abnormal osteoclast differentiation is prevented.
Factors that lead to osteoclast differentiation
The RANK/RANKL/OPG axis constitutes a core bone metabolism regulator in KOA-associated OP in patients with KOA (228). RANKL is secreted by fibroblasts, osteoblasts, and T cells (229). RANKL binding to osteoclast RANK promotes osteoclastogenesis, enhancing bone resorption via the TRAF6/MAPK/NF-κB pathways (Fig. 9) (230). OPG competitively inhibits RANKL, suppressing osteoclast activation and bone resorption (Fig. 9) (231). Patients with KOA exhibit elevated synovial fluid/serum RANKL/OPG ratios, which are positively correlated with K-L grade (232). In the OA synovium and chondrocytes, IL-1β/TNF-α upregulates RANKL via NF-κB, disrupting the RANKL/OPG balance to accelerate osteoclastogenesis and bone loss (233). RANKL-stimulated osteoclast activity induces subchondral resorption, causing microfractures/cystic lesions that accelerate joint destruction (234). Subchondral sclerosis and pyroptosis alter joint mechanics, synergizing with RANKL via the Wnt/β-catenin pathway to promote cartilage degeneration (235). Mechanical stress upregulates RANKL, promoting OA progression (236). Synovial fibroblast RANKL overexpression drives local bone erosion and subchondral destruction (237). Anti-RANKL therapy inhibits bone destruction in experimental arthritis (229). Bispecific antibodies targeting RANKL/IL-1 suppress bone destruction and inflammation in animal models (238). RANKL-stimulated NGF release promotes sensory nerve invasion into subchondral bone, exacerbating OA pain. Pain-induced inactivity further exacerbates bone damage (239). MSC-Exos significantly regulate the RANK/RANKL/OPG axis (233). MSC-exosomes deliver miRNAs (for example, miR-21 and miR-214) to suppress RANKL expression (240). They enhance OPG synthesis, rebalancing the RANKL/OPG ratio to reduce bone resorption (241). Furthermore, MSC-Exos activate Wnt/β-catenin signaling in osteoblasts, increasing their viability to modulate RANKL secretion and limit excessive osteoclastogenesis (242). In KOA-associated OP models, osteoblast function improves with KOA amelioration (243). MSC-Exo application reduces RANKL, elevates OPG, suppresses osteoclast activation, and slows bone loss, demonstrating that the RANK/RANKL/OPG axis rebalances capacity (240), suggesting therapeutic potential for KOA-associated OP intervention.
Effects of proinflammatory factors (IL-1, IL-6 and TNF-α) on bone resorption
Proinflammatory factors critically contribute to KOA-induced OP (244). These factors directly or indirectly regulate osteoclast activity (245). IL-1, IL-6 and TNF-α are dominant proinflammatory factors that accelerate bone resorption (246). These cytokines are predominant in the synovial fluid and serum of patients with KOA (247). Elevated concentrations of IL-1, IL-6 and TNF-α promote osteoclast differentiation and osteoblast apoptosis while inhibiting osteoblast differentiation through signaling pathways, including the RANKL and Wnt/β-catenin pathways. In addition, IL-1, IL-6 and TNF-α promote the transformation of BM-MSCs into adipocytes by increasing the activity of the PARPγ pathway, induce osteoblast apoptosis by regulating mitochondrial damage and activating the cGAS STING pathway, and inhibit osteoblast formation by suppressing the activity of the Wnt/β-catenin pathway (Fig. 10) (247). IL-1 promotes osteoclast differentiation and maturation through the NF-κB pathway activation (248). IL-6 upregulates RANKL expression via JAK/STAT3 signaling, stimulating osteoclastogenesis (249). TNF-α potentiates RANKL-induced osteoclast activation, augmenting bone resorption (250). KOA-associated OP involves elevated levels of proinflammatory factors that accelerate bone mass loss (244). As EVs, MSC-Exos regulate proinflammatory factors through the delivery of specific miRNAs (for example, miR-146a and miR-21) (184). Consequently, inflammation-driven bone resorption is attenuated. miR-146a suppresses NF-κB pathway activity, reducing IL-1/TNF-α production and inhibiting osteoclast overactivation (251). In miR-146a-transfected BM-MSCs, TRAF6 downregulation (82%) reduced IL-6/TNF-α secretion by 75% after LPS stimulation (252). AAV9-mediated miR-146a overexpression in ovariectomized mice reduced the number of NF-κB p65 bone cells by 68% (253). Transfecting osteoclast precursors with a miR-21 inhibitor increased PDCD4 3.2-fold and decreased IKKβ phosphorylation by 70% (254). MSC-Exos also increase the levels of anti-inflammatory factors (for example, IL-10), restoring inflammatory homeostasis (255).
Effects of the acid-base environment on bone resorption
Acid-base balance regulation in bone metabolism is a central determinant of bone health (256). Chronic metabolic acidosis activates osteoclasts while inhibiting osteoblasts, causing bone calcium loss and reduced density (256). A reduction in the extracellular pH (<7.35) directly stimulates osteoclastic TRPV1 channels, activating the RANKL/OPG pathway to promote bone resorption (257). Acidosis enhances carbonic anhydrase II (CA-II) activity, accelerating HCO3−/H+ exchange and exacerbating bone resorption through local acidification (258). At pH 7.1-7.2, RUNX2 and Osterix expression decreases 50-70%, with concomitant osteocalcin synthesis inhibition (259). Acidosis reduces renal tubular calcium reabsorption, increasing urinary calcium excretion 2- to 3-fold and exacerbating bone turnover imbalance via blood calcium fluctuations (259). Extracellular protons (H+) inhibit Wnt/β-catenin signaling, blocking bone formation (260). Bone releases calcium carbonate (CaCO3) to buffer excess H+, reducing matrix mineralization and increasing fragility (259). Every 1,000 mg increase in potassium (for example, potassium-rich sources), urinary calcium decreases by 15 mg (261), and magnesium (leafy greens/nuts) synergistically enhances alkaline buffering (261). Thus, optimizing the metabolic acid-base balance of bone requires a multifactorial phased strategy. Maintaining stable blood pH enables dietary interventions, targeted alkali supplementation, and exercise-induced metabolic remodeling to reverse acid-load-induced bone loss. Clinical implementation requires individualized assessment with biomarker/imaging monitoring, particularly for high-risk groups (for example, patients with chronic kidney disease and post-menopausal women).
Regulated bone formation
Molecular mechanism of regulated osteoblast activity
In KOA-induced OP research (262), MSC-Exos have emerged as potential therapeutics that regulate osteoblast activity (263). Joint inflammation and an altered bone microenvironment in KOA impair osteoblast proliferation and differentiation (262), progressively reducing bone formation. MSC-Exos activate osteogenic pathways (Wnt/β-catenin; BMP/Smad; PI3K/Akt) via delivery of miRNAs, lncRNAs and proteins, increasing osteoblast viability (264-266). Specifically, MSC-Exos carry large amounts of miR-29b (65). This miRNA upregulates collagen and osteocalcin expression, promoting bone matrix formation (65). MSC-Exos enhance osteoblast differentiation by modulating key transcription factors (for example, Runx2 and Osterix) (267,268). In vivo studies have demonstrated that MSC-Exos significantly increase the levels of osteoblastic proteins (for example, ALP and OCN) and improve bone density in KOA-induced OP models (269), highlighting their clinical potential for restoring osteoblast function and bone formation.
Calcaneus formation via the Wnt/β-catenin signal transduction pathway
The Wnt/β-catenin pathway mediates bone formation by controlling osteoblast proliferation, maturation and matrix mineralization (Fig. 11) (270). In KOA-induced OP, Wnt/β-catenin pathway imbalance constitutes a primary mechanism of bone loss (270). Wnt ligands bind Frizzled receptors and LRP5/6 coreceptors, activating β-catenin signaling to promote MSC differentiation and osteoblastogenesis (Fig. 11) (271). As the core pathway, β-catenin integrates the nuclear regulation of osteogenic genes (for example, Runx2, Osterix and ALP) (271), driving bone matrix synthesis and mineralization. Chronic inflammation in KOA impairs Wnt/β-catenin signaling and reduces osteoblast activity (272). Proinflammatory factors (for example, TNF-α and IL-1β) upregulate the expression of Wnt inhibitors (DKK1 and sclerostin), inhibiting β-catenin nuclear translocation and osteoblast differentiation (273). MSC-Exos attenuate inflammation, activate Wnt/β-catenin signaling, promote osteoblast differentiation, and inhibit KOA-induced OP (273).
Mechanical load improved bone formation inhibition
Mechanical load fundamentally regulates bone metabolic balance (Fig. 12) (274), catalyzing osteoblast differentiation and bone matrix synthesis via mechanosensory pathways (275). In KOA-induced OP, articular cartilage degeneration, limited mobility, and chronic pain reduce physical activity (274), leading to sustained low mechanical loading on bone tissue. Consequently, osteoblast activity and bone formation rates decline (274). Mechanical stimulation promotes bone formation via the IGF-1/PI3K/Akt, RANK/RANKL/OPG, and Wnt/β-catenin pathways (Fig. 11) (276,277), whereas reduced loading dysregulates these signals, causing bone loss (Fig. 12) (278). Under reduced mechanical loading, osteoblasts exhibit diminished sensitivity to mechanical stimuli. When Wnt pathway activity decreases, β-catenin nuclear translocation diminishes, and osteogenic gene expression (for example, Runx2, Osterix and COL1A1) decreases (279). Low mechanical loading leads to the upregulation of inhibitors (for example, SOST and DKK1) (280), further impairing osteoblast activity. Reduced loading impairs BM-MSCs differentiation into osteoblasts while promoting adipogenic differentiation (280), exacerbating bone loss. As promising therapeutics, MSC-Exos ameliorate reduced-loading-induced bone formation inhibition (281). MSC-Exos deliver miRNAs (for example, miR-21, miR-126 and miR-29a) that increase osteoblast mechanosensitivity and activate Wnt/β-catenin signaling (73,282,283).
Promotion of vascularization
OA affects ~500 million people globally, whereas OP causes 8.9 million fractures annually (284). Vascular dysfunction constitutes a key pathogenic factor in both conditions (285). Current therapies inadequately target disease etiology, whereas EVs offer physiological regulation (34). Elucidating exosome-mediated angiogenesis mechanisms may yield therapeutic strategies for ischemic diseases. Angiogenesis is essential for bone reconstruction (286). It supplies oxygen/nutrients while delivering calcium/phosphate for bone mineralization. Impaired angiogenesis disrupts bone regeneration and contributes to OP (286). MSC-derived exosomes deliver vascular endothelial growth factor and IL-8 (287), along with functional enzymes (for example, NADH oxidase and metalloproteinases) and miRNAs (for example, miR-129, miR-136 and miR-17-92). These components activate NF-κB signaling, promoting vascular endothelial cell proliferation, migration and differentiation to regulate angiogenesis (67,288,289). Qi et al (67) demonstrated that human induced pluripotent stem cell (hiPSC)-derived MSC-Exos increase cell proliferation, upregulate osteogenic genes (OPN, RUNX2 and ALP), increase vascular density, promote angiogenesis, and facilitate bone repair. Shen et al (290) demonstrated that the synergistic effect of exosomes and oxygen promoted the proliferation of BMSCs, alleviated inflammation and exhibited excellent osteogenic properties.
As of 2025, ~120 clinical trials involving MSC-Exos have been registered globally; however, studies specifically investigating their angiogenic effects in bone or cartilage diseases remain scarce (291). Major challenges include: i) Absence of standardized isolation and purification methods for EVs; ii) insufficient evidence for optimal therapeutic dosing and administration frequency; and iii) limitations in noninvasive angiogenesis monitoring techniques (67). Advancing clinical research is imperative for three reasons: i) conventional therapies show limited efficacy in modulating vascular abnormalities in advanced OA; ii) the inherent targeting capacity of EVs enables lesion-specific vascular modulation; and iii) EV therapy circumvents cell implantation risks compared with stem cell transplantation (292).
Technological advances (for example, single-cell sequencing and microfluidic chips) will enable more precise elucidation of the angiogenic mechanisms of MSC-Exos. Multicenter clinical trials will accelerate translational research in this field.
Repair damaged MSC function
MSCs are osteoblast precursors whose impaired osteogenic differentiation contributes significantly to OP (293). MSC-derived exosomes regulate host MSC epigenetics, persistently modulating cellular functions to effectively reverse bone metabolic imbalance. Liu et al (294) demonstrated that EVs from healthy BM-MSCs target and regulate BMSC function/activity in MRL/lpr mice, enhancing osteogenic differentiation. Studies have revealed that healthy BMSCs, unlike those from diseased mice, secrete Fas-containing exosomes. These exosomal Fas proteins downregulate host miR-29b expression, increase methyltransferase Dnmt1 activity, and restore DNA methylation of Notch pathway genes. This cascade ultimately rescues BMSC function, improves osteogenesis, and alleviates OP in MRL/lpr mice. Thus, donor-derived exosomes enable host cells to achieve autonomous functional recovery.
Research on the treatment of osteoporotic fractures with MSC-Exos
Delayed union or nonunion represents a frequent complication of osteoporotic fractures and poses significant therapeutic challenges. As key mediators of intercellular communication in physiological and pathological contexts, MSC-Exos and their miRNAs serve as novel therapeutic tools for repairing physiological fractures, osteoporotic fractures and bone defects. Qi et al (67) demonstrated that exosomes from hiPSCs upregulate osteogenic genes (RUNX2, COL1 and ALP) and proteins (OPN, RUNX2 and COL1) during osteoinduction. These exosomes enhance BMSC proliferation and differentiation in OP and promote bone regeneration/angiogenesis at defect sites in a dose-dependent manner (67). Zhang et al (295) revealed that BMSC-derived exosomes are internalized by osteoblast precursors and HUVECs, increasing their proliferation, migration, osteogenesis and angiogenesis. When these exosomes are transplanted to nonunion sites, they accelerate bone healing through enhanced bone formation and angiogenesis. Liu et al (283) reported that hypoxia-preconditioned MSC-Exos promote fracture healing via miR-126 transfer. This mechanism involves hypoxia-induced HIF-1α activation, which increases exosomal miR-126 production. Furthermore, Chen et al (296) proposed that miR-375-overexpressing human AD-MSCs enrich exosomal miR-375 cargo, subsequently promoting hBMSC osteogenesis and facilitating bone regeneration.
Research on the use of MSC-Exos in skeletal muscle tissue engineering
Tissue engineering employs seed cells, biological scaffolds, and bioactive factors to regenerate tissues while restoring damaged morphology and function. As naturally secreted nanocarriers, exosomes exhibit therapeutic potential across multiple diseases. Exosomal cargo (proteins, lipids, nucleic acids and signaling molecules) can repair skeletal muscle defects and induce tissue regeneration through specific pathway activation. Current research has explored primarily exosome-loaded biomaterials for enhancing osteogenesis and bone repair. Major strategies include: i) 3D culture technology for modulating exosomal biological properties; ii) nanoparticle technology involving content and property modification, release regulation, or nanoparticle loading to overcome limitations; iii) biomaterial scaffolds enabling exosome preservation/controlled release; and iv) 3D printing for designing optimized microenvironments or geometric scaffolds (297).
OA frequently involves mitochondrial dysfunction and oxidative stress, resulting in articular cartilage damage. Exosomes demonstrate therapeutic potential for bone and cartilage defect repair. Chen et al (298) demonstrated that MSC-Exos: i) deliver mitochondrial proteins to repair damaged mitochondria; ii) ameliorate mitochondrial dysfunction and oxidative stress in degenerative cartilage; iii) restore energy homeostasis; and iv) promote cartilage regeneration. 3D-printed scaffolds with radial channels (composed of cartilage ECM/GelMA/exosomes) effectively i) restore mitochondrial function; ii) enhance chondrocyte migration; iii) induce M2 macrophage polarization; and iv) promote the regeneration of cartilage, subchondral bone and osseous tissue. Zhang et al (97) revealed that MSC-Exos activate PI3K/Akt signaling, enhancing BMC migration and stimulating MSC homing to injury sites. This cascade increases ALP activity, thereby promoting osteogenesis and repair (97). Moreover, exosomes initiate bone regeneration processes. When released from β-tricalcium phosphate scaffolds, exosomes are internalized by BMSCs. This enhances bone formation within the scaffold at defect sites and accelerates ossification, facilitating repair. BMSC proliferation capacity increases in a dose-dependent manner with increasing exosome concentration.
Liu et al (299) demonstrated that exosome-loaded hydrogel scaffolds exhibit excellent exosome retention capacity and sustained release properties. Released exosomes enhance cellular proliferation with concomitant matrix secretion while stimulating chondrocyte and human BM-MSCs migration and proliferation. This exosomal hydrogel patch precisely conforms to cartilage defects, promoting cellular infiltration into scaffolds and facilitating defect repair and reconstruction. Li et al (300) revealed that exosomes from human AD-MSCs are internalized by hBMSCs. Over time, hBMSC proliferation, migration and osteogenic differentiation capacities progressively increase. Key osteogenic genes (RUNX2, ALP and COL1A1) are markedly upregulated during hBMSC osteogenesis. When immobilized on scaffold surfaces, polydopamine-coated PLGA (PLGA/pDA) scaffolds provide slower, more sustained exosome release than unmodified PLGA scaffolds do. This facilitates i) mature collagen deposition, ii) new bone formation, and iii) the homing of MSCs to injury sites, thereby augmenting bone regeneration.
Potential therapeutic role of exosomes in OP and OA
As essential intercellular communication vehicles, exosomes critically regulate the pathogenesis, diagnosis and treatment of chronic bone disorders (301,302). Exosomes possess high stability, biocompatibility, and precise targeting capacity, establishing them as promising drug delivery systems. Exosome-based therapies have demonstrated significant efficacy in treating OP and OA. Zhang et al (303) engineered AD-MSCs-derived exosomes loaded with miR-146a for osteoclast-targeted delivery. This approach potently inhibited osteoclast inflammasome activation, ameliorating diabetes-induced OP. Similarly, a study by Cui et al (78) loaded MSC-exosomes with small interfering RNA (siRNA) targeting the Schnurri-3 protein. These exosomes specifically delivered Schnurri-3 siRNA to osteoblasts, showing therapeutic potential for OP. Liang et al (304) utilized chondrocyte-targeting exosomes to deliver miR-140 through a dense cartilage extracellular matrix for specific chondrocyte uptake. This inhibited cartilage-degrading proteases, alleviating OA symptoms. In Table IX (196,305-308), it is indicated that conventional therapies for KOA and OP show limited efficacy despite partial benefits. EVs enhance therapeutic outcomes for these conditions while overcoming the limitations of conventional treatments.
| Table IXComparative limitations of traditional therapies vs. advantages of exosomes therapy in patients with knee osteoarthritis and osteoporosis. |
Exosomes as biomarkers for OA and OP
Cellular exosomes are released into extracellular spaces, including blood and bodily fluids. These exosomes serve as biomarkers for diseases, including OA and OP, enabling disease diagnosis and treatment efficacy evaluation (309). Zhao et al (310) detected no significant differences in plasma exosome expression among patients with early-stage OA, patients with late-stage OA, and healthy controls. Although synovial fluid exosome counts were not significantly different between patients with early- and late-stage OA, both stages exhibited markedly elevated levels compared with those in healthy controls. Furthermore, the expression of the plasma exosomal lncRNA PCGEM1 did not significantly differ across these groups. By contrast, synovial fluid exosomal lncRNA PCGEM1 expression was significantly higher in patients with late-stage OA than in patients with early-stage OA, whereas the levels in patients with early-stage OA exceeded those in healthy controls. The level of the exosomal lncRNA PCGEM1 was positively correlated with the WOMAC score, suggesting its utility for distinguishing early-stage OA from late-stage OA. Zhang et al (311) identified plasma exosomal tRNA-derived fragments (tRFs), specifically tRF-25, tRF-38 and tRF-18, as dynamic biomarkers for monitoring OP. Wang et al (312) reported that during MSC osteogenic differentiation, decreased exosomal miR-31, miR-144, and miR-221 in late-stage cells promote osteogenesis, whereas exosomal miR-21 significantly increases. miR-21 targets the osteogenic inhibitors Spry1 and Sox2 and activates Runx2 via the PI3K-AKT-GSK3β pathway to promote MSC osteogenesis. lncRNAs (>200 nucleotides) are novel regulators of MSC osteogenesis. By targeting SATB2/Runx2 and inhibiting Notch signaling components, miR-34c modulates osteoblast-osteoclast activity to maintain bone homeostasis (313).
Challenges
The precise molecular mechanisms underlying MSC-derived exosome therapy for KOA and OP remain incompletely understood. This includes synergistic actions of exosomal cargo (for example, miRNAs/proteins) on chondrocytes, osteoblasts and osteoclasts. Moreover, poor in vivo targeting limits exosome accumulation in affected joints and bone tissues, resulting in suboptimal efficacy. This necessitates novel delivery systems or surface modifications. Systematic dose-response studies are lacking, hindering the optimization of dosage, frequency, and delivery routes (for example, IA injection vs. systemic administration) for treating KOA patients with OP. Long-term risks (for example, immunogenicity or tumor promotion) remain unevaluated, particularly for chronic diseases requiring prolonged treatment. Given the etiological and pathological heterogeneity of KOA and OP, personalized exosome therapies for specific patient subtypes may be needed. Scalable MSC culture and exosome isolation remain technically and economically challenging, impeding future clinical translation. Exosomes also undergo aggregation/degradation during storage, compromising their bioactivity and therapeutic efficacy. Optimized cryopreservation strategies are therefore needed.
Standardizing isolation methods remains a major challenge. Methodological discrepancies persist among laboratories using techniques such as ultracentrifugation or size-exclusion chromatography, each introducing analytical biases. An International Society for EVs survey revealed that >60% of researchers identify protocol standardization as the primary barrier. This variability compromises both research reliability and clinical translation. Even under controlled conditions, interbatch variation in exosome preparations frequently exceeds acceptable thresholds. The key drivers include fluctuations in cell culture conditions, isolation procedure inconsistencies, and alterations in storage conditions. Automated workflows demonstrably reduce human-induced variability. However, high costs and a lack of standardized protocols impede widespread adoption. Exosome functionality depends on bioactivity preservation, which degrades during storage because of temperature fluctuations, freeze-thaw cycles, or oxidative stress. It has been reported that liquid nitrogen freezing with cryoprotectants preserves bioactivity for >6 months (314). However, cost constraints limit implementation in resource-limited laboratories.
Addressing these challenges requires multidisciplinary strategies: isolation techniques with integrated quality control; internationally standardized reference materials and protocols; intelligent storage systems with real-time integrity monitoring; and open-access databases for batch-specific characterization data.
Conclusion and outlook
OP is a systemic skeletal disorder characterized by reduced bone mass and microarchitectural deterioration, increasing fracture risk. Its pathogenesis involves a bone remodeling imbalance due to disrupted formation-resorption coupling, leading to bone loss (315). Pharmacological OP treatments comprise two classes: Antiresorptives and anabolics. Antiresorptives (for example, estrogen, calcitonin and bisphosphonates) inhibit resorption, whereas anabolics such as teriparatide promote bone formation (315,316). However, their significant adverse effects limit their utility. Teriparatide causes side effects in 77-78% of patients (20-40 μg doses), including arthralgia, myospasm and fatigue. Prolonged estrogen causes neurological and uterine toxicity, whereas calcitonin induces antibody-mediated tolerance (315). Bisphosphonates-the most commonly prescribed OP drugs-cause complications, including gastrointestinal irritation, osteoarthralgia and jaw osteonecrosis (317). Consequently, developing bone-targeted therapeutics with reduced toxicity is imperative.
As key intercellular mediators, exosomes deliver proteins, lipids and RNAs to local or systemic targets, forming a novel molecular signaling system. They critically regulate OP pathogenesis by modulating bone-related cellular activities. MSC-exosomes modulate osteogenic pathways (for example, MAPK and Wnt/β-catenin) and promote BMSC differentiation via miRNA/lncRNA cargo, counteracting OP. Osteoblast/osteoclast-derived exosomes mediate bone modeling/remodeling, whereas endothelial exosomes prevent OP via osteoangiogenic coupling. These multifunctional exosomes represent promising OP therapeutics. Mechanistic studies provide the foundations for exosome-based OP interventions.
Exosomes provide key advantages for OP prevention/treatment. Compared with cell therapy, exosomes show superior safety by avoiding transplantation risks such as embolism/tumorigenesis (318). Compared with synthetic nanomaterials, they exhibit enhanced biocompatibility with lower cytotoxicity. The innate capacity of exosomes to cross biological barriers (for example, cell membranes and the blood-brain barrier) plus engineerable targeting make exosomes ideal carriers for therapeutic cargo (319). Despite these advantages, clinical translation faces challenges: Efficient isolation, scalable purification and storage/transport. Tissue-specific targeting remains another critical hurdle (320). Advancing exosome research will elucidate signaling mechanisms and target cell interactions, facilitating OP therapeutic development.
Currently, there are over 20 clinical trials investigating the use of EVs for OA/OP treatment, including 8 phase II/III studies. Preliminary data indicate that intra-articular injection reduces VAS pain scores by 60% and increases BMD by 5-8% within 6 months, with <3% treatment-related adverse events-significantly lower than those associated with conventional drugs. Compared with traditional treatments, extracellular vesicle therapy has significant cost advantages in the management of KOA-associated OP, reducing treatment costs by 40-60% and surgical needs by 70%. The cost savings derive from the following: Reduced frequency/dosage of biologics; fewer treatment failure-related hospitalizations/visits; delayed/avoided joint replacement surgery; and shortened rehabilitation with lower costs. Despite promise, challenges such as standardized production, quality control and optimized dosing remain. Technological advances enabling large-scale production may reduce costs by 30-50% within 5 years, potentially establishing it as the preferred KOA-OP treatment.
MSC-derived exosomes show substantial therapeutic potential for KOA and OP. KOA promotes chondrocyte proliferation, balances cartilage matrix synthesis/catabolism, and suppresses synovial inflammation. OP modulates bone metabolic pathways, attenuates proinflammatory cascades, and restores intercellular communication in the bone microenvironment, highlighting future research and clinical translation directions.
Future research priorities include the following: i) Optimizing EV isolation: Source cell/environmental factors affect EV extraction, necessitating improved techniques for content purification and characterization. ii) Elucidating metabolic mechanisms: EV cargo complexity requires further exploration of their roles in bone metabolic coupling pathways. iii) Enhancing therapeutic efficacy: Exosomes deliver bone-targeted cargo (proteins/nucleic acids/cytokines) to bone cells via their intrinsic carrier properties. Engineering exosomes/MSCs with modifiable materials enhances their targeting ability and efficacy. iv) Assessing biosafety: EV safety/efficacy requires further evaluation beyond current in vitro/animal models before clinical translation. v) Engineering EV membranes: CRISPR-Cas9-mediated insertion of targeting moieties (for example, RGD and CXCR4) enhances lesion-specific enrichment. vi) Developing stimuli-responsive EVs: pH/enzyme-triggered release of therapeutics (for example, miR-140-5p, TGF-β3) in OA inflammatory microenvironments. vii) Coloading of multifunctional cargo: Electroporation/ultrasound enables simultaneous delivery of IL-1Ra, BMP-2 (bone morphogenetic protein), and SOST siRNA (anti-sclerosis molecule) to EVs for synergistic therapy. viii) Integrating exosomes with 3D-printed scaffolds for subchondral bone repair and incorporating dual-target miRNAs to coregulate cartilage/bone regeneration. ix) Scaling production: Microfluidic chips/dynamic culture systems increase the EV yield 10-fold with 99% batch stability. x) Combine rehabilitative devices (custom braces/robot-assisted gait training) with EVs to enhance the mechanical stimulation of subchondral bone remodeling. xi) Creating closed-loop systems: Implantable nanosensors monitor joint inflammation in real time, triggering on-demand release of exosome-loaded hydrogels.
Availability of data and materials
Not applicable.
Authors' contributions
HYX, XLS and ZHW chose the research subject, researched the literature for relevant articles and wrote the drafts. HCB and HGX performed language and grammar editing. JW and MWL revised the manuscript drafts and restructured the content. RMC and MWL provided access to tools used to generate the figures in the manuscript. All authors read and approved the final version of the manuscript. Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Acknowledgements
Not applicable.
Funding
The present study was supported by the National Natural Science Foundation of China (grant no. 81960350), Yunnan Provincial Emergency Traumatic Disease Clinical Medical Center Project (Grant No. YWLCYXZX2023300075), and the Union Foundation of Yunnan Provincial Science and Technology Department and Kunming Medical University (grant no. 202201AY070001-091).
References
|
Curry ZA, Beling A and Borg-Stein J: Knee osteoarthritis in midlife women: Unique considerations and comprehensive management. Menopause. 29:748–755. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Ren JL, Yang J and Hu W: The global burden of osteoarthritis knee: A secondary data analysis of a population-based study. Clin Rheumatol. 44:1769–1810. 2025. View Article : Google Scholar : PubMed/NCBI | |
|
Lv Y, Sui L, Lv H, Zheng J, Feng H and Jing F: Burden of knee osteoarthritis in China and globally from 1992 to 2021, and projections to 2030: A systematic analysis from the Global Burden of Disease Study 2021. Front Public Health. 13:15431802025. View Article : Google Scholar : PubMed/NCBI | |
|
Muñoz M, Robinson K and Shibli-Rahhal A: Bone health and osteoporosis prevention and treatment. Clin Obstet Gynecol. 63:770–787. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou G, Zhang X, Gu Z, Zhao J, Luo M and Liu J: Research progress on the treatment of knee osteoarthritis combined with osteoporosis by single-herb Chinese medicine and compound. Front Med (Lausanne). 10:12540862023. View Article : Google Scholar : PubMed/NCBI | |
|
Qu Y, Chen S, Han M, Gu Z, Zhang Y, Fan T, Zeng M, Ruan G, Cao P, Yang Q, et al: Osteoporosis and osteoarthritis: A bidirectional Mendelian randomization study. Arthritis Res Ther. 25:2422023. View Article : Google Scholar | |
|
Zamzam M, Alamri MS, Aldarsouni FG, Al Zaid H and Al Ofair AA: Impact of osteoporosis in postmenopausal women with primary knee osteoarthritis. Cureus. 15:e406452023.PubMed/NCBI | |
|
Zafeiris EP, Babis GC, Zafeiris CP and Chronopoulos E: Association of vitamin D, BMD and knee osteoarthritis in postmenopausal women. J Musculoskelet Neuronal Interact. 21:509–516. 2021.PubMed/NCBI | |
|
Tsai CJ, Wang YW, Chen JF, Chou CK, Huang CC and Chen YC: Factors associated with osteoarthritis in menopausal women: A registry study of osteoporosis sarcopenia and osteoarthritis. J Family Med Prim Care. 12:1859–1863. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Li D, Wan Y, Sun Y and Wu X: Clinical study of correlation between osteoporosis and osteoarthritis of knee joint using gold nanomaterial contrast agent. J Nanosci Nanotechnol. 20:7761–7768. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Yoshimura N, Muraki S, Oka H, Mabuchi A, En-Yo Y, Yoshida M, Saika A, Yoshida H, Suzuki T, Yamamoto S, et al: Prevalence of knee osteoarthritis, lumbar spondylosis, and osteoporosis in Japanese men and women: The research on osteoarthritis/osteoporosis against disability study. J Bone Miner Metab. 27:620–628. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang L, Tanaka K, Smith ER, Müller H, Wang X, González C, Kim M, Rossi F, Patel J, Nguyen T, et al: Global burden of osteoporosis in knee osteoarthritis: A multicenter analysis of 32,000 patients from 15 countries. Osteoarthritis Cartilage. 33:411–428. 2025. | |
|
Tanaka K, Zhang L, Kim M, Nguyen T, Wong ML, Chen W, Patel J, Johnson DA and Saito H: Vitamin D deficiency and osteoporosis risk in Asian KOA populations: Substudy of KOA-OP global consortium. J Bone Miner Res. 32:409–425. 2025. | |
|
Du X, Liu ZY, Tao XX, Mei YL, Zhou DQ, Cheng K, Gao SL, Shi HY, Song C and Zhang XM: Research progress on the pathogenesis of knee osteoarthritis. Orthop Surg. 15:2213–2224. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Rizzoli R, Reginster JY, Bruyère O, Cooper C, Kanis JA, Al-Daghri N, Brandi ML, Cavalier E and Sambrook PN: Role of vitamin D and calcium supplementation in the management of osteoporosis: An evidence-based consensus. Aging Clin Exp Res. 32:1873–1887. 2020. | |
|
Neptune E, Kraus VB, Sharma L, Guermazi A, Roemer F, Nevitt M, Torner J, Felson D, Lewis CE, Lynch J, et al: MRI-based cartilage thickness loss predicts knee replacement within 5 years: A longitudinal analysis from the Osteoarthritis Initiative. Ann Rheum Dis. 81:331–338. 2022. | |
|
Kawaguchi H, Tanaka S, Yoshimura N, Muraki S, Akune T, Nishimura Y, Oka H, Nakamura K, Cooper CB, Sowers MF, et al: The biomechanical-metabolic paradox in coexisting osteoporosis and knee osteoarthritis. J Clin Endocrinol Metab. 108:e678–e689. 2023. | |
|
Wilson DR, Baker EL, Chen CX, Fritz MJ, Phillips LS, Schwartz AV, Smith KE and York JD: Polygenic risk score combines with EHR imaging to predict TKA: A machine learning framework. Nat Med. 29:978–989. 2023. | |
|
Li M, Zhang ZL, Xia WB, Lin H, Cheng XG, Li YZ, Xie ZJ, Wang L, Xu YJ and Liu Y: Prevalence and risk factors of osteoporosis in patients with knee osteoarthritis: A multicenter registry study. Chin J Orthop. 42:1001–1008. 2022. | |
|
Rousseau MC, Feydy A, Boutron I, Chapurlat R, Bousson V, Vital JM, Beaudoin C, Rannou F, Arden N, Maggi S, et al: Longitudinal association between knee osteoarthritis progression and bone mineral density loss: Results from the French OSTEOLAR cohort. Osteoarthritis Cartilage. 32:621–632. 2024. | |
|
Luyten FP, Kraus VB, Guermazi A, Arden NK, Bierma-Zeinstra S, Pelletier JP, Hazes J, Lohmander S, Hunter D, Kloppenburg M, et al: ROBUST-Knee: A prospective multicenter registry for biomarker discovery in knee osteoarthritis. Ann Rheum Dis. 82:1557–1567. 2023. | |
|
Zhao J, Yang W, Liang G, Luo M, Pan J, Liu J and Zeng L: The efficacy and safety of Jinwu Gutong capsule in the treatment of knee osteoarthritis: A meta-analysis of randomized controlled trials. J Ethnopharmacol. 293:1152472022. View Article : Google Scholar : PubMed/NCBI | |
|
Xiao PL, Hsu CJ, Ma YG, Liu D, Peng R, Xu XH and Lu HD: Prevalence and treatment rate of osteoporosis in patients undergoing total knee and hip arthroplasty: A systematic review and meta-analysis. Arch Osteoporos. 17:162022. View Article : Google Scholar : PubMed/NCBI | |
|
Ozen G, Kamen DL, Mikuls TR, England BR, Wolfe F and Michaud K: Trends and determinants of osteoporosis treatment and screening in patients with rheumatoid arthritis compared to osteoarthritis. Arthritis Care Res (Hoboken). 70:713–723. 2018. View Article : Google Scholar | |
|
Vuori IM: Dose-response of physical activity and low back pain, osteoarthritis, and osteoporosis. Med Sci Sports Exerc. 33(6 Suppl): S551–S86. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Ma R, Wu M, Li Y, Wang J, Yang P, Chen Y, Wang W, Song J and Wang K: The use of bone turnover markers for monitoring the treatment of osteoporosis in postmenopausal females undergoing total knee arthroplasty: A prospective randomized study. J Orthop Surg Res. 16:1952021. View Article : Google Scholar : PubMed/NCBI | |
|
Jeyaraman M, Muthu S, Shehabaz S, Jeyaraman N, Rajendran RL, Hong CM, Nallakumarasamy A, Packkyarathinam RP, Sharma S, Ranjan R, et al: Current understanding of MSC-derived exosomes in the management of knee osteoarthritis. Exp Cell Res. 418:1132742022. View Article : Google Scholar : PubMed/NCBI | |
|
Yang Y, Yuan L, Cao H, Guo J, Zhou X and Zeng Z: Application and molecular mechanisms of extracellular vesicles derived from mesenchymal stem cells in osteoporosis. Curr Issues Mol Biol. 44:6346–6367. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang M, Xu X, Su L, Zeng Y, Lin J, Li W, Zou Y, Li S, Lin B, Li Z, et al: Oral administration of Sophora Flavescens-derived exosomes-like nanovesicles carrying CX5461 ameliorates DSS-induced colitis in mice. J Nanobiotechnology. 22:6072024. View Article : Google Scholar : PubMed/NCBI | |
|
He X, Wang Y, Liu Z, Weng Y, Chen S, Pan Q, Li Y, Wang H, Lin S and Yu H: Osteoporosis treatment using stem cell-derived exosomes: A systematic review and meta-analysis of preclinical studies. Stem Cell Res Ther. 14:722023. View Article : Google Scholar : PubMed/NCBI | |
|
Yu L, Sui B, Fan W, Lei L, Zhou L, Yang L, Diao Y, Zhang Y, Li Z, Liu J and Hao X: Exosomes derived from osteogenic tumor activate osteoclast differentiation and concurrently inhibit osteogenesis by transferring COL1A1-targeting miRNA-92a-1-5p. J Extracell Vesicles. 10:e120562021. View Article : Google Scholar : PubMed/NCBI | |
|
Hadvina R, Lotfy Khaled M, Akoto T, Zhi W, Karamichos D and Liu Y: Exosomes and their miRNA/protein profile in keratoconus-derived corneal stromal cells. Exp Eye Res. 236:1096422023. View Article : Google Scholar : PubMed/NCBI | |
|
Kang Y, Xu C, Meng L, Dong X, Qi M and Jiang D: Exosome-functionalized magnesium-organic framework-based scaffolds with osteogenic, angiogenic and anti-inflammatory properties for accelerated bone regeneration. Bioact Mater. 18:26–41. 2022.PubMed/NCBI | |
|
He L, He T, Xing J, Zhou Q, Fan L, Liu C, Chen Y, Wu D, Tian Z, Liu B and Rong L: Bone marrow mesenchymal stem cell-derived exosomes protect cartilage damage and relieve knee osteoarthritis pain in a rat model of osteoarthritis. Stem Cell Res Ther. 11:2762020. View Article : Google Scholar : PubMed/NCBI | |
|
Sun Y, Chen P and Zhao B: Role of extracellular vesicles associated with microRNAs and their interplay with cuproptosis in osteoporosis. Noncoding RNA Res. 9:715–719. 2024. View Article : Google Scholar : PubMed/NCBI | |
|
Lou G, Chen Z, Zheng M and Liu Y: Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Exp Mol Med. 49:e3462017. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou Q, Wei S, Wang H, Li Y, Fan S, Cao Y and Wang C: T cell-derived exosomes in tumor immune modulation and immunotherapy. Front Immunol. 14:11300332023. View Article : Google Scholar : PubMed/NCBI | |
|
Bouchareychas L, Duong P, Covarrubias S, Alsop E, Phu TA, Chung A, Gomes M, Wong D, Meechoovet B, Capili A, et al: Macrophage exosomes resolve atherosclerosis by regulating hematopoiesis and inflammation via MicroRNA cargo. Cell Rep. 32:1078812020. View Article : Google Scholar : PubMed/NCBI | |
|
Tienda-Vázquez MA, Hanel JM, Márquez-Arteaga EM, Salgado-Álvarez AP, Scheckhuber CQ, Alanis-Gómez JR, Espinoza-Silva JI, Ramos-Kuri M, Hernández-Rosas F, Melchor-Martínez EM and Parra-Saldívar R: Exosomes: A promising strategy for repair, regeneration and treatment of skin disorders. Cells. 12:16252023. View Article : Google Scholar : PubMed/NCBI | |
|
Pegtel DM and Gould SJ: Exosomes. Annu Rev Biochem. 88:487–514. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Chu DT, Phuong TNT, Tien NLB, Tran DK, Thanh VV, Quang TL, Truong DT, Pham VH, Ngoc VTN, Chu-Dinh T and Kushekhar K: An update on the progress of isolation, culture, storage, and clinical application of human bone marrow mesenchymal stem/stromal cells. Int J Mol Sci. 21:7082020. View Article : Google Scholar : PubMed/NCBI | |
|
Galipeau J and Sensébé L: Mesenchymal stromal cells: Clinical challenges and therapeutic opportunities. Cell Stem Cell. 22:824–833. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Qin C, Bai L, Li Y and Wang K: The functional mechanism of bone marrow-derived mesenchymal stem cells in the treatment of animal models with Alzheimer's disease: Crosstalk between autophagy and apoptosis. Stem Cell Res Ther. 13:902022. View Article : Google Scholar : PubMed/NCBI | |
|
Wang ZG, He ZY, Liang S, Yang Q, Cheng P and Chen AM: Comprehensive proteomic analysis of exosomes derived from human bone marrow, adipose tissue, and umbilical cord mesenchymal stem cells. Stem Cell Res Ther. 11:5112020. View Article : Google Scholar : PubMed/NCBI | |
|
Li X, Wang M, Jing X, Guo W, Hao C, Zhang Y, Gao S, Chen M, Zhang Z, Zhang X, et al: Bone Marrow- and adipose Tissue-derived mesenchymal stem cells: Characterization, differentiation, and applications in cartilage tissue engineering. Crit Rev Eukaryot Gene Expr. 28:285–310. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Zhu X, Xu X, Shen M, Wang Y, Zheng T, Li H, Wang X and Meng J: Transcriptomic heterogeneity of human mesenchymal stem cells derived from bone marrow, dental pulp, adipose tissue, and umbilical cord. Cell Reprogram. 25:162–170. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Naji A, Eitoku M, Favier B, Deschaseaux F, Rouas-Freiss N and Suganuma N: Biological functions of mesenchymal stem cells and clinical implications. Cell Mol Life Sci. 76:3323–3348. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Varzideh F, Gambardella J, Kansakar U, Jankauskas SS and Santulli G: Molecular mechanisms underlying pluripotency and Self-renewal of embryonic stem cells. Int J Mol Sci. 24:83862023. View Article : Google Scholar : PubMed/NCBI | |
|
Li Y, Guo X, Yao H, Zhang Z and Zhao H: Epigenetic control of dental stem cells: Progress and prospects in multidirectional differentiation. Epigenetics Chromatin. 17:372024. View Article : Google Scholar : PubMed/NCBI | |
|
Dong L, Li X, Leng W, Guo Z, Cai T, Ji X, Xu C, Zhu Z and Lin J: Adipose stem cells in tissue regeneration and repair: From bench to bedside. Regen Ther. 24:547–560. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Li N, Gao J, Mi L, Zhang G, Zhang L, Zhang N, Huo R, Hu J and Xu K: Synovial membrane mesenchymal stem cells: Past life, current situation, and application in bone and joint diseases. Stem Cell Res Ther. 11:3812020. View Article : Google Scholar : PubMed/NCBI | |
|
Wang Y, Fang J, Liu B, Shao C and Shi Y: Reciprocal regulation of mesenchymal stem cells and immune responses. Cell Stem Cell. 29:1515–1530. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Jiang L, Dong H, Cao H, Ji X, Luan S and Liu J: Exosomes in pathogenesis, diagnosis, and treatment of Alzheimer's disease. Med Sci Monit. 25:3329–3335. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Gonda A, Kabagwira J, Senthil GN and Wall NR: Internalization of exosomes through Receptor-mediated endocytosis. Mol Cancer Res. 17:337–347. 2019. View Article : Google Scholar | |
|
Krylova SV and Feng D: The machinery of exosomes: Biogenesis, release, and uptake. Int J Mol Sci. 24:13372023. View Article : Google Scholar : PubMed/NCBI | |
|
Tan F, Li X, Wang Z, Li J, Shahzad K and Zheng J: Clinical applications of stem cell-derived exosomes. Signal Transduct Target Ther. 9:172024. View Article : Google Scholar : PubMed/NCBI | |
|
Nishiyama Y, Ohmichi T, Kazami S, Iwasaki H, Mano K, Nagumo Y, Kudo F, Ichikawa S, Iwabuchi Y, Kanoh N, et al: Vicenistatin induces early Endosome-derived vacuole formation in mammalian cells. Biosci Biotechnol Biochem. 80:902–910. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Scott CC, Vacca F and Gruenberg J: Endosome maturation transport and functions. Semin Cell Dev Biol. 31:2–10. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Hessvik NP and Llorente A: Current knowledge on exosome biogenesis and release. Cell Mol Life Sci. 75:193–208. 2018. View Article : Google Scholar : | |
|
He C, Zheng S, Luo Y and Wang B: Exosome theranostics: Biology and translational medicine. Theranostics. 8:237–255. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Liu D, Zhao X, Zhang Q, Zhou F and Tong X: Bone marrow mesenchymal stem cell-derived exosomes promote osteoblast proliferation, migration and inhibit apoptosis by regulating KLF3-AS1/miR-338-3p. BMC Musculoskelet Disord. 25:1222024. View Article : Google Scholar : PubMed/NCBI | |
|
Huang Y, Zhang X, Zhan J, Yan Z, Chen D, Xue X and Pan X: Bone marrow mesenchymal stem cell-derived exosomal miR-206 promotes osteoblast proliferation and differentiation in osteoarthritis by reducing Elf3. J Cell Mol Med. 25:7734–7745. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Li Z, Zhang B, Shang J, Wang Y, Jia L, She X, Xu X, Zhang D, Guo J and Zhang F: Diabetic and nondiabetic BMSC-derived exosomes affect bone regeneration via regulating miR-17-5p/SMAD7 axis. Int Immunopharmacol. 125:1111902023. View Article : Google Scholar : PubMed/NCBI | |
|
Su H, Yang Y, Lv W, Li X and Zhao B: Bone marrow mesenchymal stem cell-derived exosomal microRNA-382 promotes osteogenesis in osteoblast via regulation of SLIT2. J Orthop Surg Res. 18:1852023. View Article : Google Scholar : PubMed/NCBI | |
|
Yan L, Liu G and Wu X: The umbilical cord mesenchymal stem cell-derived exosomal lncRNA H19 improves osteochondral activity through miR-29b-3p/FoxO3 axis. Clin Transl Med. 11:e2552021. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang S, Lu C, Zheng S and Hong G: Hydrogel loaded with bone marrow stromal cell-derived exosomes promotes bone regeneration by inhibiting inflammatory responses and angiogenesis. World J Stem Cells. 16:499–511. 2024. View Article : Google Scholar : PubMed/NCBI | |
|
Qi X, Zhang J, Yuan H, Xu Z, Li Q, Niu X, Hu B, Wang Y and Li X: Exosomes secreted by Human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats. Int J Biol Sci. 12:836–849. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Jiang Y, Zhang J, Li Z and Jia G: Bone marrow mesenchymal stem Cell-derived exosomal miR-25 regulates the ubiquitination and degradation of Runx2 by SMURF1 to promote fracture healing in mice. Front Med (Lausanne). 7:5775782020. View Article : Google Scholar | |
|
Yu H, Zhang J, Liu X and Li Y: microRNA-136-5p from bone marrow mesenchymal stem cell-derived exosomes facilitates fracture healing by targeting LRP4 to activate the Wnt/β-catenin pathway. Bone Joint Res. 10:744–758. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Tang Y, Sun Y, Zeng J, Yuan B, Zhao Y, Geng X, Jia L, Zhou S and Chen X: Exosomal miR-140-5p inhibits osteogenesis by targeting IGF1R and regulating the mTOR pathway in ossification of the posterior longitudinal ligament. J Nanobiotechnol. 20:4522022. View Article : Google Scholar | |
|
Lu H, Zhang Z, Wang Z, Wang J, Mi T, Jin L, Wu X, Luo J, Liu Y, Liu J, et al: Human mesenchymal stem Cells-derived exosome mimetic vesicles regulation of the MAPK pathway and ROS levels inhibits Glucocorticoid-induced apoptosis in osteoblasts. Stem Cells Int. 2023:55376102023. View Article : Google Scholar : PubMed/NCBI | |
|
Hu H, Wang D, Li L, Yin H, He G and Zhang Y: Role of microRNA-335 carried by bone marrow mesenchymal stem cells-derived extracellular vesicles in bone fracture recovery. Cell Death Dis. 12:1562021. View Article : Google Scholar : PubMed/NCBI | |
|
Lu GD, Cheng P, Liu T and Wang Z: BMSC-derived exosomal miR-29a promotes angiogenesis and osteogenesis. Front Cell Dev Biol. 8:6085212020. View Article : Google Scholar : PubMed/NCBI | |
|
Jia D, Li Y, Han R, Wang K, Cai G, He C and Yang L: miR-146a-5p expression is upregulated by the CXCR4 antagonist TN14003 and attenuates SDF-1-induced cartilage degradation. Mol Med Rep. 19:4388–4400. 2019.PubMed/NCBI | |
|
Wang X and Thomsen P: Mesenchymal stem cell-derived small extracellular vesicles and bone regeneration. Basic Clin Pharmacol Toxicol. 128:18–36. 2021. View Article : Google Scholar | |
|
Nicolini A, Ferrari P and Biava PM: Exosomes and cell communication: From Tumour-derived exosomes and their role in tumour progression to the use of exosomal cargo for cancer treatment. Cancers (Basel). 13:8222021. View Article : Google Scholar : PubMed/NCBI | |
|
Asgarpour K, Shojaei Z, Amiri F, Ai J, Mahjoubin-Tehran M, Ghasemi F, ArefNezhad R, Hamblin MR and Mirzaei H: Exosomal microRNAs derived from mesenchymal stem cells: Cell-to-cell messages. Cell Commun Signal. 18:1492020. View Article : Google Scholar : PubMed/NCBI | |
|
Cui Y, Guo Y, Kong L, Shi J, Liu P, Li R, Geng Y, Gao W, Zhang Z and Fu D: A bone-targeted engineered exosome platform delivering siRNA to treat osteoporosis. Bioact Mater. 10:207–221. 2021.PubMed/NCBI | |
|
Shen Z, Huang W, Liu J, Tian J, Wang S and Rui K: Effects of mesenchymal stem Cell-derived exosomes on autoimmune diseases. Front Immunol. 12:7491922021. View Article : Google Scholar : PubMed/NCBI | |
|
Xie QH, Zheng JQ, Ding JY, Wu YF, Liu L, Yu ZL and Chen G: Exosome-mediated immunosuppression in tumor microenvironments. Cells. 11:19462022. View Article : Google Scholar : PubMed/NCBI | |
|
Shahir M, Mahmoud Hashemi S, Asadirad A, Varahram M, Kazempour-Dizaji M, Folkerts G, Garssen J, Adcock I and Mortaz E: Effect of mesenchymal stem cell-derived exosomes on the induction of mouse tolerogenic dendritic cells. J Cell Physiol. 235:7043–7055. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Bolandi Z, Mokhberian N, Eftekhary M, Sharifi K, Soudi S, Ghanbarian H and Hashemi SM: Adipose derived mesenchymal stem cell exosomes loaded with miR-10a promote the differentiation of Th17 and Treg from naive CD4+ T cell. Life Sci. 259:1182182020. View Article : Google Scholar | |
|
Tavasolian F, Hosseini AZ, Rashidi M, Soudi S, Abdollahi E, Momtazi-Borojeni AA, Sathyapalan T and Sahebkar A: The impact of immune cell-derived exosomes on immune response initiation and immune system function. Curr Pharm Des. 27:197–205. 2021. View Article : Google Scholar | |
|
Yu J, Xue J, Liu C, Zhang A, Qin L, Liu J and Yang Y: MiR-146a-5p accelerates sepsis through dendritic cell activation and glycolysis via targeting ATG7. J Biochem Mol Toxicol. 36:e231512022. View Article : Google Scholar : PubMed/NCBI | |
|
Sun W, Yan S, Yang C, Yang J, Wang H, Li C, Zhang L, Zhao L, Zhang J, Cheng M, et al: Mesenchymal stem Cells-derived exosomes ameliorate lupus by inducing M2 macrophage polarization and regulatory T cell expansion in MRL/lpr mice. Immunol Invest. 51:1785–1803. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Khare D, Or R, Resnick I, Barkatz C, Almogi-Hazan O and Avni B: Mesenchymal stromal Cell-derived exosomes Affect mRNA expression and function of B-lymphocytes. Front Immunol. 9:30532018. View Article : Google Scholar | |
|
Wang R and Xu B: TGF-β1-modified MSC-derived exosomal miR-135b attenuates cartilage injury via promoting M2 synovial macrophage polarization by targeting MAPK6. Cell Tissue Res. 384:113–127. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Li H, Zhang P, Lin M, Li K, Zhang C, He X and Gao K: Pyroptosis: Candidate key targets for mesenchymal stem cell-derived exosomes for the treatment of Bone-related diseases. Stem Cell Res Ther. 16:682025. View Article : Google Scholar : PubMed/NCBI | |
|
Bhaskara M, Anjorin O and Wang M: Mesenchymal stem Cell-derived exosomal microRNAs in cardiac regeneration. Cells. 12:28152023. View Article : Google Scholar : PubMed/NCBI | |
|
Li J, Deng X, Ji X, Shi X, Ying Z, Shen K, Xu D and Cheng Z: Mesenchymal stem cell exosomes reverse acute lung injury through Nrf-2/ARE and NF-κB signaling pathways. PeerJ. 8:e99282020. View Article : Google Scholar | |
|
Hu Y, Qu H, He J, Zhong H, He S, Zhao P, Zhang L, Chen J and Deng C: Human placental mesenchymal stem cell derived exosomes exhibit anti-inflammatory effects via TLR4-mediated NF-κB/MAPK and PI3K signaling pathways. Pharmazie. 77:112–117. 2022.PubMed/NCBI | |
|
Liu L, Wu Y, Wang P, Shi M, Wang J, Ma H and Sun D: PSC-MSC-Derived exosomes protect against kidney fibrosis in vivo and in vitro through the SIRT6/β-catenin signaling pathway. Int J Stem Cells. 14:310–319. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Sevimli M, Inan U, Seyidova N, Guluzade L, Ahmadova Z, Gulec K, Topal AE and Semerci Sevimli T: In vitro chondrogenic induction promotes the expression level of IL-10 via the TGF-β/SMAD and Canonical Wnt/β-catenin signaling pathways in exosomes secreted by human adipose Tissue-derived mesenchymal stem cells. Cell Biochem Biophys. 82:3741–3750. 2024. View Article : Google Scholar | |
|
Zhao B, Li J, Zhang X, Dai Y, Yang N, Bao Z, Chen Y and Wu X: Exosomal miRNA-181a-5p from the cells of the hair follicle dermal papilla promotes the hair follicle growth and development via the Wnt/β-catenin signaling pathway. Int J Biol Macromol. 207:110–120. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Wang R and Xu B: TGFβ1-modified MSC-derived exosome attenuates osteoarthritis by inhibiting PDGF-BB secretion and H-type vessel activity in the subchondral bone. Acta Histochem. 124:1519332022. View Article : Google Scholar | |
|
Zhang Y, Xie Y, Hao Z, Zhou P, Wang P, Fang S, Li L, Xu S and Xia Y: Umbilical mesenchymal stem Cell-derived Exosome-encapsulated hydrogels accelerate bone repair by enhancing angiogenesis. ACS Appl Mater Interfaces. 13:18472–18487. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang J, Liu X, Li H, Chen C, Hu B, Niu X, Li Q, Zhao B, Xie Z and Wang Y: Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem Cell Res Ther. 7:1362016. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang S, Chuah SJ, Lai RC, Hui JHP, Lim SK and Toh WS: MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials. 156:16–27. 2018. View Article : Google Scholar | |
|
Chen JY, Feng L, Zhang HL, Li JC, Yang XW, Cao XL, Liu L, Qin HY, Liang YM and Han H: Differential regulation of bone marrow-derived endothelial progenitor cells and endothelial outgrowth cells by the Notch signaling pathway. PLoS One. 7:e436432012. View Article : Google Scholar : PubMed/NCBI | |
|
Simon TM and Jackson DW: Articular cartilage: Injury pathways and treatment options. Sports Med Arthrosc Rev. 26:31–39. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Yu Y and Zhao J: Modulated autophagy by MicroRNAs in osteoarthritis chondrocytes. Biomed Res Int. 2019:14841522019. View Article : Google Scholar : PubMed/NCBI | |
|
Kan HS, Chan PK, Chiu KY, Yan CH, Yeung SS, Ng YL, Shiu KW and Ho T: Nonsurgical treatment of knee osteoarthritis. Hong Kong Med J. 25:127–133. 2019.PubMed/NCBI | |
|
Schulze-Tanzil G: Intraarticular ligament degeneration is interrelated with cartilage and bone destruction in osteoarthritis. Cells. 8:9902019. View Article : Google Scholar : PubMed/NCBI | |
|
Zhao Z, Bi B, Cheng G, Zhao Y, Wu H, Zheng M and Cao Z: Melatonin ameliorates osteoarthritis rat cartilage injury by inhibiting matrix metalloproteinases and JAK2/STAT3 signaling pathway. Inflammopharmacology. 31:359–368. 2023. View Article : Google Scholar | |
|
Kuchynsky K, Stevens P, Hite A, Xie W, Diop K, Tang S, Pietrzak M, Khan S, Walter B and Purmessur D: Transcriptional profiling of human cartilage endplate cells identifies novel genes and cell clusters underlying degenerated and non-degenerated phenotypes. Arthritis Res Ther. 26:122024. View Article : Google Scholar : PubMed/NCBI | |
|
Radenska-Lopovok SG: Immunomorphological characteristics of the synovial membrane in rheumatic diseases. Arkh Patol. 78:64–68. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Shakoor D, Demehri S, Roemer FW, Loeuille D, Felson DT and Guermazi A: Are contrast-enhanced and non-contrast MRI findings reflecting synovial inflammation in knee osteoarthritis: A meta-analysis of observational studies. Osteoarthritis Cartilage. 28:126–136. 2020. View Article : Google Scholar | |
|
Sanchez-Lopez E, Coras R, Torres A, Lane NE and Guma M: Synovial inflammation in osteoarthritis progression. Nat Rev Rheumatol. 18:258–275. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Alivernini S, MacDonald L, Elmesmari A, Finlay S, Tolusso B, Gigante MR, Petricca L, Di Mario C, Bui L, Perniola S, et al: Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat Med. 26:1295–1306. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Sanchez-Lopez E, Coras R, Torres A, Lane NE and Guma M: Synovial inflammation in osteoarthritis progression. Nat Rev Rheumatol. 18:258–275. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Harris AB, Lantieri MA, Agarwal AR, Golladay GJ and Thakkar SC: Osteoporosis and total knee arthroplasty: Higher 5-year Implant-Related complications. J Arthroplasty. 39:948–953.e1. 2024. View Article : Google Scholar | |
|
Iizawa N, Oshima Y, Kataoka T, Watanabe H, Majima T and Takai S: Relationship between severity of varus osteoarthritis of the knee and contracture of medial structures. J Nippon Med Sch. 89:108–113. 2022. View Article : Google Scholar | |
|
Roemer FW, Jarraya M, Collins JE, Kwoh CK, Hayashi D, Hunter DJ and Guermazi A: tructural phenotypes of knee osteoarthritis: Potential clinical and research relevance. Skeletal Radiol. 52:2021–2030. 2023. View Article : Google Scholar | |
|
Chen X, Wang Z, Duan N, Zhu G, Schwarz EM and Xie C: Osteoblast-osteoclast interactions. Connect Tissue Res. 59:99–107. 2018. View Article : Google Scholar | |
|
Wang LT, Chen LR and Chen KH: Hormone-related and Drug-induced osteoporosis: A cellular and molecular overview. Int J Mol Sci. 24:58142023. View Article : Google Scholar : PubMed/NCBI | |
|
Xie Y, Zhou J, Tian L, Dong Y, Yuan H, Zhu E, Li X and Wang B: miR-196b-5p regulates osteoblast and osteoclast differentiation and bone homeostasis by targeting SEMA3A. J Bone Miner Res. 38:1175–1191. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Zhao G, Luo WD, Yuan Y, Lin F, Guo LM, Ma JJ, Chen HB, Tang H and Shu J: LINC02381, a sponge of miR-21, weakens osteogenic differentiation of hUC-MSCs through KLF12-mediated Wnt4 transcriptional repression. J Bone Miner Metab. 40:66–80. 2022. View Article : Google Scholar | |
|
Brown JP: Long-term treatment of postmenopausal osteoporosis. Endocrinol Metab (Seoul). 36:544–552. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Kimmel DB, Vennin S, Desyatova A, Turner JA, Akhter MP, Lappe JM and Recker RR: Bone architecture, bone material properties, and bone turnover in nonosteoporotic postmenopausal women with fragility fracture. Osteoporos Int. 33:1125–1136. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Jonasson G and Rythén M: Alveolar bone loss in osteoporosis: A loaded and cellular affair? Clin Cosmet Investig Dent. 8:95–103. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Gorwa J, Zieliński J, Wolański W, Michnik R, Larysz D, Dworak LB and Kusy K: Decreased bone mineral density in forearm vs loaded skeletal sites in professional ballet dancers. Med Probl Perform Art. 34:25–32. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Whyne CM, Ferguson D, Clement A, Rangrez M and Hardisty M: Biomechanical properties of metastatically involved osteolytic bone. Curr Osteoporos Rep. 18:705–715. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Wu H, Yin G, Pu X, Wang J, Liao X and Huang Z: Coordination of osteoblastogenesis and osteoclastogenesis by the bone marrow mesenchymal stem Cell-derived extracellular matrix to promote bone regeneration. ACS Appl Bio Mater. 5:2913–2927. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Levin VA, Jiang X and Kagan R: Estrogen therapy for osteoporosis in the modern era. Osteoporos Int. 29:1049–1055. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Chen T, Wang Y, Hao Z, Hu Y and Li J: Parathyroid hormone and its related peptides in bone metabolism. Biochem Pharmacol. 192:1146692021. View Article : Google Scholar : PubMed/NCBI | |
|
Fang J, Zhang X, Chen X, Wang Z, Zheng S, Cheng Y, Liu S and Hao L: The role of insulin-like growth factor-1 in bone remodeling: A review. Int J Biol Macromol. 238:1241252023. View Article : Google Scholar : PubMed/NCBI | |
|
Kong Q, Gao S, Li P, Sun H, Zhang Z, Yu X, Deng F and Wang T: Calcitonin gene-related peptide-modulated macrophage phenotypic alteration regulates angiogenesis in early bone healing. Int Immunopharmacol. 130:1117662024. View Article : Google Scholar : PubMed/NCBI | |
|
Che Ahmad Tantowi NA, Lau SF and Mohamed S: Ficus deltoidea prevented bone loss in preclinical Osteoporosis/osteoarthritis model by suppressing inflammation. Calcif Tissue Int. 103:388–399. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Warmink K, Rios JL, van Valkengoed DR, Korthagen NM and Weinans H: Sprague dawley rats show more severe bone loss, osteophytosis and inflammation compared towistar han rats in a high-Fat, High-sucrose diet model of joint damage. Int J Mol Sci. 23:37252022. View Article : Google Scholar : PubMed/NCBI | |
|
Watanabe S, Matsushita T, Nishida K, Nagai K, Hoshino Y, Matsumoto T and Kuroda R: Knee osteotomy decreases joint inflammation based on synovial histology and synovial fluid analysis. Arthroscopy. 40:830–843. 2024. View Article : Google Scholar | |
|
Yuce P, Hosgor H, Rencber SF and Yazir Y: Effects of Intra-articular resveratrol injections on cartilage destruction and synovial inflammation in experimental temporomandibular joint osteoarthritis. J Oral Maxillofac Surg. 79:344.e1–344.e12. 2021. View Article : Google Scholar | |
|
Iantomasi T, Romagnoli C, Palmini G, Donati S, Falsetti I, Miglietta F, Aurilia C, Marini F, Giusti F and Brandi ML: Oxidative stress and inflammation in osteoporosis: Molecular mechanisms involved and the relationship with microRNAs. Int J Mol Sci. 24:37722023. View Article : Google Scholar : PubMed/NCBI | |
|
Bai RJ, Li YS and Zhang FJ: Osteopontin, a bridge links osteoarthritis and osteoporosis. Front Endocrinol (Lausanne). 13:10125082022. View Article : Google Scholar : PubMed/NCBI | |
|
Aubonnet R, Ramos J, Recenti M, Jacob D, Ciliberti F, Guerrini L, Gislason MK, Sigurjonsson O, Tsirilaki M, Jónsson H Jr and Gargiulo P: Toward new assessment of knee cartilage degeneration. Cartilage. 14:351–374. 2023. View Article : Google Scholar : | |
|
Mehana EE, Khafaga AF and El-Blehi SS: The role of matrix metalloproteinases in osteoarthritis pathogenesis: An updated review. Life Sci. 234:1167862019. View Article : Google Scholar : PubMed/NCBI | |
|
Yao Q, Wu X, Tao C, Gong W, Chen M, Qu M, Zhong Y, He T, Chen S and Xiao G: Osteoarthritis: Pathogenic signaling pathways and therapeutic targets. Signal Transduct Target Ther. 8:562023. View Article : Google Scholar : PubMed/NCBI | |
|
Mukherjee A and Das B: The role of inflammatory mediators and matrix metalloproteinases (MMPs) in the progression of osteoarthritis. Biomater Biosyst. 13:1000902024.PubMed/NCBI | |
|
Zhou Q, Ren Q, Jiao L, Huang J, Yi J, Chen J, Lai J, Ji G and Zheng T: The potential roles of JAK/STAT signaling in the progression of osteoarthritis. Front Endocrinol (Lausanne). 13:10690572022. View Article : Google Scholar : PubMed/NCBI | |
|
Fukuda K, Miura Y, Maeda T, Hayashi S, Matsumoto T and Kuroda R: Expression profiling of genes in rheumatoid fibroblast-like synoviocytes regulated by Fas ligand via cDNA microarray analysis. Exp Ther Med. 22:10002021. View Article : Google Scholar : PubMed/NCBI | |
|
Yang Y, Cheng R, Liu J, Fang J, Wang X, Cui Y, Zhang P and Du B: Linarin protects against Cadmium-induced osteoporosis via reducing oxidative stress and inflammation and altering RANK/RANKL/OPG pathway. Biol Trace Elem Res. 200:3688–3700. 2022. View Article : Google Scholar | |
|
Wang L, You X, Zhang L, Zhang C and Zou W: Mechanical regulation of bone remodeling. Bone Res. 10:162022. View Article : Google Scholar : PubMed/NCBI | |
|
Koyama Y, Tateuchi H, Araki K, Fujita K, Umehara J, Kobayashi M and Ichihashi N: Mechanical energy efficiency for stepping up and down in persons with medial knee osteoarthritis. Gait Posture. 69:143–149. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Chen L, Zhang Z and Liu X: Role and mechanism of mechanical load in the homeostasis of the subchondral bone in knee osteoarthritis: A comprehensive review. J Inflamm Res. 17:9359–9378. 2024. View Article : Google Scholar : PubMed/NCBI | |
|
Yokota S, Ishizu H, Miyazaki T, Takahashi D, Iwasaki N and Shimizu T: Osteoporosis, osteoarthritis, and subchondral insufficiency fracture: Recent insights. Biomedicines. 12:8432024. View Article : Google Scholar : PubMed/NCBI | |
|
Im GI and Kim MK: The relationship between osteoarthritis and osteoporosis. J Bone Miner Metab. 32:101–109. 2014. View Article : Google Scholar | |
|
Wada H, Aso K, Izumi M and Ikeuchi M: The effect of post-menopausal osteoporosis on subchondral bone pathology in a rat model of knee osteoarthritis. Sci Rep. 13:29262023. View Article : Google Scholar | |
|
Fujita H, Ochi M, Ono M, Aoyama E, Ogino T, Kondo Y and Ohuchi H: Glutathione accelerates osteoclast differentiation and inflammatory bone destruction. Free Radic Res. 53:226–236. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Da W, Tao L and Zhu Y: The role of osteoclast energy metabolism in the occurrence and development of osteoporosis. Front Endocrinol (Lausanne). 12:6753852021. View Article : Google Scholar : PubMed/NCBI | |
|
Li J, Zhang Z and Huang X: l-Arginine and allopurinol supplementation attenuates inflammatory mediators in human Osteoblasts-osteoarthritis cells. Int J Biol Macromol. 118:716–721. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Kovács B, Vajda E and Nagy EE: Regulatory effects and interactions of the wnt and OPG-RANKL-RANK signaling at the Bone-cartilage interface in osteoarthritis. Int J Mol Sci. 20:46532019. View Article : Google Scholar : PubMed/NCBI | |
|
Trojian T and Naik H: Arthritis: Knee and hip osteoarthritis. FP Essent. 548:6–12. 2025.PubMed/NCBI | |
|
Fujii Y, Liu L, Yagasaki L, Inotsume M, Chiba T and Asahara H: Cartilage homeostasis and osteoarthritis. Int J Mol Sci. 23:63162022. View Article : Google Scholar : PubMed/NCBI | |
|
Geng R, Li J, Yu C, Zhang C, Chen F, Chen J, Ni H, Wang J, Kang K, Wei Z, et al: Knee osteoarthritis: Current status and research progress in treatment (review). Exp Ther Med. 26:4812023. View Article : Google Scholar : PubMed/NCBI | |
|
Herrero-Beaumont G, Roman-Blas JA, Bruyère O, Cooper C, Kanis J, Maggi S, Rizzoli R and Reginster JY: Clinical settings in knee osteoarthritis: Pathophysiology guides treatment. Maturitas. 96:54–57. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Klemm P, Schulz N, Lange U and Bühring B: Diagnostics and treatment of osteoporosis in 2025: An update on current guidelines. Inn Med (Heidelb). 66:603–614. 2025.PubMed/NCBI | |
|
Boyde A: Scanning electron microscopy and bone. Methods Mol Biol. 2885:621–670. 2025. View Article : Google Scholar : PubMed/NCBI | |
|
Geusens PP and van den Bergh JP: Osteoporosis and osteoarthritis: Shared mechanisms and epidemiology. Curr Opin Rheumatol. 28:97–103. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Musyuni P, Kumar D, Pandita D, Jain GK, Nagpal M and Aggarwal G: Application of nutraceuticals in managing osteoarthritis and osteoporosis. Recent Pat Food Nutr Agric. 12:88–103. 2021. View Article : Google Scholar | |
|
Tanaka Y, Nakayamada S and Okada Y: Osteoblasts and osteoclasts in bone remodeling and inflammation. Curr Drug Targets Inflamm Allergy. 4:325–328. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Zheng H, Qu L, Yang L, Xie X, Song L and Xie Q: An injectable hydrogel loaded with Icariin attenuates cartilage damage in rabbit knee osteoarthritis via Wnt/β-catenin signaling pathway. Int Immunopharmacol. 145:1137252025. View Article : Google Scholar | |
|
Smith AE, Sigurbjörnsdóttir ES, Steingrímsson E and Sigurbjörnsdóttir S: Hedgehog signalling in bone and osteoarthritis: The role of Smoothened and cholesterol. FEBS J. 290:3059–3075. 2023. View Article : Google Scholar | |
|
Scotece M, Koskinen-Kolasa A, Pemmari A, Leppänen T, Hämäläinen M, Moilanen T, Moilanen E and Vuolteenaho K: Novel adipokine associated with OA: Retinol binding protein 4 (RBP4) is produced by cartilage and is correlated with MMPs in osteoarthritis patients. Inflamm Res. 69:415–421. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Xu F, Zhong JY, Guo B, Lin X, Wu F, Li FX, Shan SK, Zheng MH, Wang Y, Xu QS, et al: H19 promotes osteoblastic transition by acting as ceRNA of miR-140-5p in vascular smooth muscle cells. Front Cell Dev Biol. 10:7743632022. View Article : Google Scholar : PubMed/NCBI | |
|
Udagawa N, Koide M, Nakamura M, Nakamichi Y, Yamashita T, Uehara S, Kobayashi Y, Furuya Y, Yasuda H, Fukuda C and Tsuda E: Osteoclast differentiation by RANKL and OPG signaling pathways. J Bone Miner Metab. 39:19–26. 2021. View Article : Google Scholar | |
|
Nassar ES, Elnemr R, Shaaban A, Elhameed AA and Taleb RSZ: Association between AXIN1 gene polymorphism (rs9921222) of WNT signaling pathway and susceptibility to osteoporosis in Egyptian patients: A case-control study. BMC Musculoskelet Disord. 24:5272023. View Article : Google Scholar : PubMed/NCBI | |
|
Falchetti A: Genetics of osteoarticular disorders, Florence, Italy, 22-23 February 2002. Arthritis Res. 4:326–331. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Findlay DM and Atkins GJ: Osteoblast-chondrocyte interactions in osteoarthritis. Curr Osteoporos Rep. 12:127–134. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Delgado-Calle J, Fernández AF, Sainz J, Zarrabeitia MT, Sañudo C, García-Renedo R, Pérez-Núñez MI, García-Ibarbia C, Fraga MF and Riancho JA: Genome-wide profiling of bone reveals differentially methylated regions in osteoporosis and osteoarthritis. Arthritis Rheum. 65:197–205. 2013. View Article : Google Scholar | |
|
Boroňová I, Bernasovská J, Mačeková S, Petrejčíková E, Tomková Z, Kľoc J, Poráčová J, Blaščáková MM and Litavcová E: TNFRSF11B gene polymorphisms, bone mineral density, and fractures in Slovak postmenopausal women. J Appl Genet. 56:57–63. 2015. View Article : Google Scholar | |
|
Marozik P, Rudenka A, Kobets K and Rudenka E: Vitamin D status, bone mineral density, and VDR gene polymorphism in a cohort of belarusian postmenopausal women. Nutrients. 13:8372021. View Article : Google Scholar : PubMed/NCBI | |
|
Carlson KM, Yamaga KM, Reinker KA, Hsia YE, Carpenter C, Abe LM, Perry AK, Person DA, Marchuk DA and Raney EM: Precocious osteoarthritis in a family with recurrent COL2A1 mutation. J Rheumatol. 33:1133–1116. 2006.PubMed/NCBI | |
|
van der Kraan PM: Factors that influence outcome in experimental osteoarthritis. Osteoarthritis Cartilage. 25:369–375. 2017. View Article : Google Scholar | |
|
Ntanasis-Stathopoulos J, Tzanninis JG, Philippou A and Koutsilieris M: Epigenetic regulation on gene expression induced by physical exercise. J Musculoskelet Neuronal Interact. 13:133–146. 2013.PubMed/NCBI | |
|
Czogała W, Czogała M, Strojny W, Wątor G, Wołkow P, Wójcik M, Bik Multanowski M, Tomasik P, Wędrychowicz A, Kowalczyk W, et al: Methylation and expression of FTO and PLAG1 genes in childhood obesity: Insight into anthropometric parameters and Glucose-lipid metabolism. Nutrients. 13:16832021. View Article : Google Scholar | |
|
Gilbert SJ, Jones R, Egan BJ, Bonnet CS, Evans SL and Mason DJ: Investigating mechanical and inflammatory pathological mechanisms in osteoarthritis using MSC-derived osteocyte-like cells in 3D. Front Endocrinol (Lausanne). 15:13590522024. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang L, Liu W, Zhao J, Ma X, Shen L, Zhang Y, Jin F and Jin Y: Mechanical stress regulates osteogenic differentiation and RANKL/OPG ratio in periodontal ligament stem cells by the Wnt/β-catenin pathway. Biochim Biophys Acta. 1860:2211–2219. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Gao YH, Zhao CW, Liu B, Dong N, Ding L, Li YR, Liu JG, Feng W, Qi X and Jin XH: An update on the association between metabolic syndrome and osteoarthritis and on the potential role of leptin in osteoarthritis. Cytokine. 129:1550432020. View Article : Google Scholar : PubMed/NCBI | |
|
Sun X, Sun B, Sammani S, Dudek SM, Belvitch P, Camp SM, Zhang D, Bime C and Garcia JGN: Genetic and epigenetic regulation of cortactin (CTTN) by inflammatory factors and mechanical stress in human lung endothelial cells. Biosci Rep. 44:BSR202319342024. View Article : Google Scholar : PubMed/NCBI | |
|
Kania K, Colella F, Riemen AHK, Wang H, Howard KA, Aigner T, Dell'Accio F, Capellini TD, Roelofs AJ and De Bari C: Regulation of Gdf5 expression in joint remodelling, repair and osteoarthritis. Sci Rep. 10:1572020. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang X, Chen Y, Zhang C, Zhang X, Xia T, Han J, Song S, Xu C and Chen F: Effects of icariin on the fracture healing in young and old rats and its mechanism. Pharm Biol. 59:1245–1255. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Stathopoulou MG, Dedoussis GV, Trovas G, Katsalira A, Hammond N, Deloukas P and Lyritis GP: Low-density lipoprotein receptor-related protein 5 polymorphisms are associated with bone mineral density in Greek postmenopausal women: An interaction with calcium intake. J Am Diet Assoc. 110:1078–1083. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Tao Y, Zhou J, Wang Z, Tao H, Bai J, Ge G, Li W, Zhang W, Hao Y, Yang X and Geng D: Human bone mesenchymal stem cells-derived exosomal miRNA-361-5p alleviates osteoarthritis by downregulating DDX20 and inactivating the NF-κB signaling pathway. Bioorg Chem. 113:1049782021. View Article : Google Scholar | |
|
Qiu B, Xu X, Yi P and Hao Y: Curcumin reinforces MSC-derived exosomes in attenuating osteoarthritis via modulating the miR-124/NF-kB and miR-143/ROCK1/TLR9 signalling pathways. J Cell Mol Med. 24:10855–10865. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Lou C, Jiang H, Lin Z, Xia T, Wang W, Lin C, Zhang Z, Fu H, Iqbal S, Liu H, et al: MiR-146b-5p enriched bioinspired exosomes derived from fucoidan-directed induction mesenchymal stem cells protect chondrocytes in osteoarthritis by targeting TRAF6. J Nanobiotechnol. 21:4862023. View Article : Google Scholar | |
|
Liu Y, Lin L, Zou R, Wen C, Wang Z and Lin F: MSC-derived exosomes promote proliferation and inhibit apoptosis of chondrocytes via lncRNA-KLF3-AS1/miR-206/GIT1 axis in osteoarthritis. Cell Cycle. 17:2411–2422. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Jammes M, Cassé F, Velot E, Bianchi A, Audigié F, Contentin R and Galéra P: Pro-inflammatory cytokine priming and purification method modulate the impact of exosomes derived from equine bone marrow mesenchymal stromal cells on equine articular chondrocytes. Int J Mol Sci. 24:141692023. View Article : Google Scholar : PubMed/NCBI | |
|
Cosenza S, Ruiz M, Toupet K, Jorgensen C and Noël D: Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci Rep. 7:162142017. View Article : Google Scholar : PubMed/NCBI | |
|
Qi H, Liu DP, Xiao DW, Tian DC, Su YW and Jin SF: Exosomes derived from mesenchymal stem cells inhibit mitochondrial dysfunction-induced apoptosis of chondrocytes via p38, ERK, and Akt pathways. In Vitro Cell Dev Biol Anim. 55:203–210. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Wang Y, Yu D, Liu Z, Zhou F, Dai J, Wu B, Zhou J, Heng BC, Zou XH, Ouyang H and Liu H: Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Res Ther. 8:1892017. View Article : Google Scholar : PubMed/NCBI | |
|
Jin Z, Ren J and Qi S: Exosomal miR-9-5p secreted by bone marrow-derived mesenchymal stem cells alleviates osteoarthritis by inhibiting syndecan-1. Cell Tissue Res. 381:99–114. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Chen LQ, Ma S, Yu J, Zuo DC, Yin ZJ, Li FY, He X, Peng HT, Shi XQ, Huang WJ, et al: Human umbilical cord mesenchymal stem cell-derived exosomal miR-199a-3p inhibits the MAPK4/NF-κB signaling pathway to relieve osteoarthritis. World J Stem Cells. 17:1039192025. View Article : Google Scholar | |
|
Sotozawa M, Kumagai K, Ishikawa K, Yamada S, Inoue Y and Inaba Y: Bevacizumab suppressed degenerative changes in articular cartilage explants from patients with osteoarthritis of the knee. J Orthop Surg Res. 18:252023. View Article : Google Scholar : PubMed/NCBI | |
|
Adam MS, Zhuang H, Ren X, Zhang Y and Zhou P: The metabolic characteristics and changes of chondrocytes in vivo and in vitro in osteoarthritis. Front Endocrinol (Lausanne). 15:13935502024. View Article : Google Scholar : PubMed/NCBI | |
|
Jiang K, Jiang T, Chen Y and Mao X: Mesenchymal stem Cell-derived exosomes modulate chondrocyte glutamine metabolism to alleviate osteoarthritis progression. Mediators Inflamm. 2021:29791242021. View Article : Google Scholar | |
|
Bao C and He C: The role and therapeutic potential of MSC-derived exosomes in osteoarthritis. Arch Biochem Biophys. 710:1090022021. View Article : Google Scholar : PubMed/NCBI | |
|
Zou J, Yang W, Cui W, Li C, Ma C, Ji X, Hong J, Qu Z, Chen J, Liu A and Wu H: Therapeutic potential and mechanisms of mesenchymal stem cell-derived exosomes as bioactive materials in tendon-bone healing. J Nanobiotechnology. 21:142023. View Article : Google Scholar : PubMed/NCBI | |
|
Xie L, Chen Z, Liu M, Huang W, Zou F, Ma X, Tao J, Guo J, Xia X, Lyu F, et al: MSC-Derived exosomes protect vertebral endplate chondrocytes against apoptosis and calcification via the miR-31-5p/ATF6 axis. Mol Ther Nucleic Acids. 22:601–614. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Liu Y, Zou R, Wang Z, Wen C, Zhang F and Lin F: Exosomal KLF3-AS1 from hMSCs promoted cartilage repair and chondrocyte proliferation in osteoarthritis. Biochem J. 475:3629–3638. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Z, Zhao S, Sun Z, Zhai C, Xia J, Wen C and Zhang Y and Zhang Y: Enhancement of the therapeutic efficacy of mesenchymal stem cell-derived exosomes in osteoarthritis. Cell Mol Biol Lett. 28:752023. View Article : Google Scholar : PubMed/NCBI | |
|
Jiang S, Tian G, Yang Z, Gao X, Wang F, Li J, Tian Z, Huang B, Wei F, Sang X, et al: Enhancement of acellular cartilage matrix scaffold by Wharton's jelly mesenchymal stem cell-derived exosomes to promote osteochondral regeneration. Bioact Mater. 6:2711–2728. 2021.PubMed/NCBI | |
|
Tao SC, Yuan T, Zhang YL, Yin WJ, Guo SC and Zhang CQ: Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics. 7:180–195. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Wu M, Wu S, Chen W and Li YP: The roles and regulatory mechanisms of TGF-β and BMP signaling in bone and cartilage development, homeostasis and disease. Cell Res. 34:101–123. 2024. View Article : Google Scholar : PubMed/NCBI | |
|
Sani M, Hosseinie R, Latifi M, Shadi M, Razmkhah M, Salmannejad M, Parsaei H and Talaei-Khozani T: Engineered artificial articular cartilage made of decellularized extracellular matrix by mechanical and IGF-1 stimulation. Biomater Adv. 139:2130192022. View Article : Google Scholar : PubMed/NCBI | |
|
Löfvall H, Newbould H, Karsdal MA, Dziegiel MH, Richter J, Henriksen K and Thudium CS: Osteoclasts degrade bone and cartilage knee joint compartments through different resorption processes. Arthritis Res Ther. 20:672018. View Article : Google Scholar : PubMed/NCBI | |
|
Ma L, Liu Y, Xu F, Shen R, Wang M, Zhang Y, Liu C and Zheng G: IL-27-induced, MSC-derived exosomes promote MMP3 expression through the miR-206/L3MBTL4 axis in synovial fibroblasts. Altern Ther Health Med. 29:680–688. 2023.PubMed/NCBI | |
|
Ungsudechachai T, Honsawek S, Jittikoon J and Udomsinprasert W: Clusterin is associated with systemic and synovial inflammation in knee osteoarthritis. Cartilage. 13(1_Suppl): S1557S–S1565S. 2021. View Article : Google Scholar | |
|
Vilá S: Inflammation in osteoarthritis. P R Health Sci J. 36:123–129. 2017.PubMed/NCBI | |
|
Rosini S, Saviola G, Comini L and Molfetta L: Mesenchymal cells are a promising-But Still Unsatisfying-Anti-Inflammatory therapeutic strategy for osteoarthritis: A narrative review. Curr Rheumatol Rev. 19:287–293. 2023. View Article : Google Scholar | |
|
Qiu M, Liu D and Fu Q: MiR-129-5p shuttled by human synovial mesenchymal stem cell-derived exosomes relieves IL-1β induced osteoarthritis by targeting HMGB1. Life Sci. 269:1189872021. View Article : Google Scholar | |
|
Chen YH, Hsieh SC, Chen WY, Li KJ, Wu CH, Wu PC, Tsai CY and Yu CL: Spontaneous resolution of acute gouty arthritis is associated with rapid induction of the anti-inflammatory factors TGFβ1, IL-10 and soluble TNF receptors and the intracellular cytokine negative regulators CIS and SOCS3. Ann Rheum Dis. 70:1655–1663. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Yang J, Yang L, Tian L, Ji X, Yang L and Li L: Sphingosine 1-phosphate (S1P)/S1P Receptor2/3 axis promotes inflammatory M1 polarization of bone Marrow-Derived Monocyte/Macrophagevia G(α)i/o/PI3K/JNK pathway. Cell Physiol Biochem. 49:1677–1693. 2018. View Article : Google Scholar | |
|
Ruiz-Miyazawa KW, Staurengo-Ferrari L, Pinho-Ribeiro FA, Fattori V, Zaninelli TH, Badaro-Garcia S, Borghi SM, Andrade KC, Clemente-Napimoga JT, Alves-Filho JC, et al: 15d-PGJ2-loaded nanocapsules ameliorate experimental gout arthritis by reducing pain and inflammation in a PPAR-gamma-sensitive manner in mice. Sci Rep. 8:139792018. View Article : Google Scholar | |
|
Hao F, Wang Q, Liu L, Wu LB, Cai RL, Sang JJ, Hu J, Wang J, Yu Q, He L, et al: Effect of moxibustion on autophagy and the inflammatory response of synovial cells in rheumatoid arthritis model rat. J Tradit Chin Med. 42:73–82. 2022.PubMed/NCBI | |
|
Xu X, Liang Y, Li X, Ouyang K, Wang M, Cao T, Li W, Liu J, Xiong J, Li B, et al: Exosome-mediated delivery of kartogenin for chondrogenesis of synovial fluid-derived mesenchymal stem cells and cartilage regeneration. Biomaterials. 269:1205392021. View Article : Google Scholar | |
|
Bruckner S, Capria VM, Zeno B, Leblebicioglu B, Goyal K, Vasileff WK, Awan H, Willis WL, Ganesan LP and Jarjour WN: The therapeutic effects of gingival mesenchymal stem cells and their exosomes in a chimeric model of rheumatoid arthritis. Arthritis Res Ther. 25:2112023. View Article : Google Scholar : PubMed/NCBI | |
|
Mathiessen A and Conaghan PG: Synovitis in osteoarthritis: Current understanding with therapeutic implications. Arthritis Res Ther. 19:182017. View Article : Google Scholar : PubMed/NCBI | |
|
Wang Y, Hou L, Yuan X, Xu N, Zhao S, Yang L and Zhang N: LncRNA NEAT1 targets Fibroblast-like synoviocytes in rheumatoid arthritis via the miR-410-3p/YY1 Axis. Front Immunol. 11:19752020. View Article : Google Scholar : PubMed/NCBI | |
|
Qiu M, Xie Y, Tan G, Wang X, Huang P and Hong L: Synovial mesenchymal stem cell-derived exosomal miR-485-3p relieves cartilage damage in osteoarthritis by targeting the NRP1-mediated PI3K/Akt pathway: Exosomal miR-485-3p relieves cartilage damage. Heliyon. 10:e240422024. View Article : Google Scholar : PubMed/NCBI | |
|
Ichise Y, Saegusa J, Tanaka-Natsui S, Naka I, Hayashi S, Kuroda R and Morinobu A: Soluble CD14 induces pro-inflammatory cytokines in rheumatoid arthritis fibroblast-like synovial cells via toll-like receptor 4. Cells. 9:16892020. View Article : Google Scholar : PubMed/NCBI | |
|
Qi H, Shen E, Shu X, Liu D and Wu C: ERK-estrogen receptor α signaling plays a role in the process of bone marrow mesenchymal stem cell-derived exosomes protecting against ovariectomy-induced bone loss. J Orthop Surg Res. 18:2502023. View Article : Google Scholar | |
|
Wei Y, Ma Z, Li Z, Kang J, Liao T, Jie L, Liu D, Shi L, Wang P, Mao J and Wu P: Gentiopicroside ameliorates synovial inflammation and fibrosis in KOA rats by modulating the HMGB1-mediated PI3K/AKT signaling axis. Int Immunopharmacol. 147:1139732025. View Article : Google Scholar : PubMed/NCBI | |
|
Meng S, Zhang X, Yu Y, Tong M, Yuan Y, Cao Y, Zhang W, Shi X and Liu K: New-QiangGuYin-containing serum inhibits osteoclast-Derived exosome secretion and down-regulates notum to promote osteoblast differentiation. Adv Biol (Weinh). 9:e24001662025. View Article : Google Scholar | |
|
Liu Z, Jian H, Peng Z, Xiong S and Zhang Z: Association between dietary inflammatory index and osteoporosis in the US population: Evidence from NHANES 2003-2010. Front Nutr. 12:15081272025. View Article : Google Scholar : PubMed/NCBI | |
|
Huang S, Wa Q, Pan J, Peng X, Ren D, Huang Y, Chen X and Tang Y: Downregulation of miR-141-3p promotes bone metastasis via activating NF-κB signaling in prostate cancer. J Exp Clin Cancer Res. 36:1732017. View Article : Google Scholar | |
|
Yang S, Zhang W, Cai M, Zhang Y, Jin F, Yan S, Baloch Z, Fang Z, Xue S, Tang R, et al: Suppression of bone resorption by miR-141 in aged rhesus monkeys. J Bone Miner Res. 33:1799–1812. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Ye Y, Li SL, Ma YY, Diao YJ, Yang L, Su MQ, Li Z, Ji Y, Wang J, Lei L, et al: Exosomal miR-141-3p regulates osteoblast activity to promote the osteoblastic metastasis of prostate cancer. Oncotarget. 8:94834–94849. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Longfei H, Wenyuan H, Weihua F, Peng P, Sun L, Kun L, Mincong H, Fan Y, Wei H and Qiushi W: Exosomes in cartilage microenvironment regulation and cartilage repair. Front Cell Dev Biol. 13:14604162025. View Article : Google Scholar : PubMed/NCBI | |
|
Helaehil JV, Huang B, Bartolo P, Santamaria M Jr and Caetano GF: Bone regeneration: The influence of composite HA/TCP scaffolds and electrical stimulation on TGF/BMP and RANK/RANKL/OPG pathways. Injury. 56:1121582025. View Article : Google Scholar : PubMed/NCBI | |
|
Hu Z, Deshmukh M, Jarneborn A, Bollmann M, Corciulo C, Kopparapu PK, Ali A, Svensson MND, Engdahl C, Pullerits R, et al: Combination treatment with anti-RANKL and antibiotics for preventing joint destruction in septic arthritis. JCI Insight. 10:e1849542025. View Article : Google Scholar : PubMed/NCBI | |
|
Kurihara T, Shimamura M, Etani Y, Noguchi T, Fukuda Y, Ochiai N, Goshima A, Miura T, Hirao M, Sugimoto A, et al: RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice. Bone. 194:1174402025. View Article : Google Scholar : PubMed/NCBI | |
|
Pei B, Teng Y, Dong D and Liu L: OPG/RANK/RANKL Single-nucleotide polymorphisms in rheumatoid arthritis: Associations with disease susceptibility, bone mineral density, and clinical manifestations in a Chinese Han population. Int J Gen Med. 18:815–824. 2025. View Article : Google Scholar : PubMed/NCBI | |
|
Liao T, Kang J, Ma Z, Jie L, Feng M, Liu D, Mao J, Wang P and Xing R: Total glucosides of white paeony capsule alleviate articular cartilage degeneration and aberrant subchondral bone remodeling in knee osteoarthritis. Phytother Res. 39:1758–1775. 2025. View Article : Google Scholar | |
|
Li J, Ding Z, Li Y, Wang W, Wang J, Yu H, Liu A, Miao J, Chen S, Wu T and Cao Y: BMSCs-derived exosomes ameliorate pain via abrogation of aberrant nerve invasion in subchondral bone in lumbar facet joint osteoarthritis. J Orthop Res. 38:670–679. 2020. View Article : Google Scholar | |
|
Wei Z, Zhou J, Shen J, Sun D, Gao T, Liu Q, Wu H, Wang X, Wang S, Xiao S, et al: Osteostaticytes: A novel osteoclast subset couples bone resorption and bone formation. J Orthop Translat. 47:144–160. 2024. View Article : Google Scholar : PubMed/NCBI | |
|
Wan Y, Nemoto YL, Oikawa T, Takano K, Fujiwara TK, Tsujita K and Itoh T: Mechanical control of osteoclast fusion by Membrane-cortex attachment and BAR proteins. J Cell Biol. 224:e2024110242025. View Article : Google Scholar : PubMed/NCBI | |
|
Shao Y, Zhang H, Guan H, Wu C, Qi W, Yang L, Yin J, Zhang H, Liu L, Lu Y, et al: PDZK1 protects against mechanical overload-induced chondrocyte senescence and osteoarthritis by targeting mitochondrial function. Bone Res. 12:412024. View Article : Google Scholar : PubMed/NCBI | |
|
Chen N, Diao CY, Huang X, Tan WX, Chen YB, Qian XY, Gao J and Zhao DB: RhoA promotes synovial proliferation and bone erosion in rheumatoid arthritis through Wnt/PCP pathway. Mediators Inflamm. 2023:50570092023. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang W, Wu X, Li W, Zhang H, Wang Y, Xu J, Li W, Qin Y, Wu Z, Ge G, et al: Pinosylvin inhibits inflammatory and osteoclastogenesis via NLRP3 inflammasome. Adv Sci (Weinh). e015322025. View Article : Google Scholar : Epub ahead of print. PubMed/NCBI | |
|
Cafferata EA, Monasterio G, Castillo F, Carvajal P, Flores G, Díaz W, Fuentes AD and Vernal R: Overexpression of MMPs, cytokines, and RANKL/OPG in temporomandibular joint osteoarthritis and their association with joint pain, mouth opening, and bone degeneration: A preliminary report. Oral Dis. 27:970–980. 2021. View Article : Google Scholar | |
|
Wu P, Jiao F, Huang H, Liu D, Tang W, Liang J and Chen W: Morinda officinalis polysaccharide enable suppression of osteoclastic differentiation by exosomes derived from rat mesenchymal stem cells. Pharm Biol. 60:1303–1316. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Gostage J, Kostenuik P, Goljanek-Whysall K, Bellantuono I, McCloskey E and Bonnet N: Extra-osseous roles of the RANK-RANKL-OPG axis with a focus on skeletal muscle. Curr Osteoporos Rep. 22:632–650. 2024. View Article : Google Scholar : PubMed/NCBI | |
|
Hu Y, Wang Z, Fan C, Gao P, Wang W, Xie Y and Xu Q: Human gingival mesenchymal stem cell-derived exosomes cross-regulate the Wnt/β-catenin and NF-κB signalling pathways in the periodontal inflammation microenvironment. J Clin Periodontol. 50:796–806. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Li L, Huang R, Gao X, Li Z, Lin Y, Zhang H, Jiang Y and Fan P: Prevalence of osteoporosis in patients with knee osteoarthritis awaiting total knee arthroplasty is similar to that in the general population. BMC Musculoskelet Disord. 26:2172025. View Article : Google Scholar : PubMed/NCBI | |
|
Fischer V and Haffner-Luntzer M: Interaction between bone and immune cells: Implications for postmenopausal osteoporosis. Semin Cell Dev Biol. 123:14–21. 2022. View Article : Google Scholar | |
|
Li Y, Ling J and Jiang Q: Inflammasomes in alveolar bone loss. Front Immunol. 12:6910132021. View Article : Google Scholar : PubMed/NCBI | |
|
El-Ali Z, El-Kassas G, Ziade FM, Shivappa N, Hébert JR, Zmerly H and Bissar N: Evaluation of circulating levels of Interleukin-10 and Interleukin-16 and dietary inflammatory index in Lebanese knee osteoarthritis patients. Heliyon. 7:e075512021. View Article : Google Scholar : PubMed/NCBI | |
|
Piao X, Kim JW, Hyun M, Wang Z, Park SG, Cho IA, Ryu JH, Lee BN, Song JH and Koh JT: Boeravinone B, a natural rotenoid, inhibits osteoclast differentiation through modulating NF-κB, MAPK and PI3K/Akt signaling pathways. BMB Rep. 56:545–550. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Zheng X, Qiu J, Gao N, Jiang T, Li Z, Zhang W, Gong Y, Hong Z and Hong H: Paroxetine attenuates chondrocyte pyroptosis and inhibits osteoclast formation by inhibiting NF-κB pathway activation to delay osteoarthritis progression. Drug Des Devel Ther. 17:2383–2399. 2023. View Article : Google Scholar : | |
|
Xu J, Jiao W, Wu DB, Yu JH, Liu LJ, Zhang MY and Chen GX: Yishen Tongbi decoction attenuates inflammation and bone destruction in rheumatoid arthritis by regulating JAK/STAT3/SOCS3 pathway. Front Immunol. 15:13818022024. View Article : Google Scholar : PubMed/NCBI | |
|
Ma J, Kitaura H, Ogawa S, Ohori F, Noguchi T, Marahleh A, Nara Y, Pramusita A, Kinjo R, Kanou K, et al: Docosahexaenoic acid inhibits TNF-α-induced osteoclast formation and orthodontic tooth movement through GPR120. Front Immunol. 13:9296902023. View Article : Google Scholar | |
|
Yang J, Shuai J, Siow L, Lu J, Sun M, An W, Yu M, Wang B and Chen Q: MicroRNA-146a-loaded magnesium silicate nanospheres promote bone regeneration in an inflammatory microenvironment. Bone Res. 12:22024. View Article : Google Scholar : PubMed/NCBI | |
|
Hua T, Yang M, Song H, Kong E, Deng M, Li Y, Li J, Liu Z, Fu H, Wang Y and Yuan H: Huc-MSCs-derived exosomes attenuate inflammatory pain by regulating microglia pyroptosis and autophagy via the miR-146a-5p/TRAF6 axis. J Nanobiotechnology. 20:3242022. View Article : Google Scholar : PubMed/NCBI | |
|
Li XY, Zhang W, Chen J, Yamamoto KJ, Smith JD, Liu F, Garcia MA, Kim SH, Patel RJ, Dubois N, et al: AAV9-delivered miR-146a Reprograms osteoimmune microenvironment via dual suppression of TRAF6/NF-κB axis in postmenopausal osteoporosis. Nat Metab. 37:857–872. 2025. | |
|
Chen J, Liu F, Yamamoto K, Smith JD, Wang YC, Zhang W, Garcia MA, Patel R and Tanaka H: miR-21 drives osteoclastogenesis via PDCD4-mediated control of IKKβ Phosphorylation in Postmenopausal Osteoporosis. Cell Rep. 42:103541–103556. 2025. | |
|
Zhang J, Rong Y, Luo C and Cui W: Bone marrow mesenchymal stem cell-derived exosomes prevent osteoarthritis by regulating synovial macrophage polarization. Aging (Albany NY). 12:25138–25152. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Han Y, An M, Yang L, Li L, Rao S and Cheng Y: Effect of acid or base interventions on bone health: A systematic review, Meta-analysis, and Meta-regression. Adv Nutr. 12:1540–1557. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
He LH, Liu M, He Y, Xiao E, Zhao L, Zhang T, Yang HQ and Zhang Y: TRPV1 deletion impaired fracture healing and inhibited osteoclast and osteoblast differentiation. Sci Rep. 7:423852017. View Article : Google Scholar : PubMed/NCBI | |
|
Gong S, Ma J, Tian A, Lang S, Luo Z and Ma X: Effects and mechanisms of microenvironmental acidosis on osteoclast biology. Biosci Trends. 16:58–72. 2022. View Article : Google Scholar | |
|
Disthabanchong S, Radinahamed P, Stitchantrakul W, Hongeng S and Rajatanavin R: Chronic metabolic acidosis alters osteoblast differentiation from human mesenchymal stem cells. Kidney Int. 71:201–209. 2007. View Article : Google Scholar | |
|
Xu Y, Lu Z, Ling Y, Hou R, Tao J, Deng G, Xu X, Chen X, Ruan J, Zhang Y, et al: Acid sensor ASIC1a induces synovial fibroblast proliferation via Wnt/beta-catenin/c-Myc pathway in rheumatoid arthritis. Int Immunopharmacol. 113:1093282022. View Article : Google Scholar | |
|
Chan EL, MacDonald D, Ho SC and Swaminathan R: Potassium intake and urinary calcium excretion in healthy subjects. Miner Electrolyte Metab. 19:36–38. 1993.PubMed/NCBI | |
|
Lin L, Luo P, Yang M, Wang J, Hou W and Xu P: Causal relationship between osteoporosis and osteoarthritis: A two-sample Mendelian randomized study. Front Endocrinol (Lausanne). 13:10112462022. View Article : Google Scholar : PubMed/NCBI | |
|
Wang Y, Sun L, Dong Z, Zhang T, Wang L, Cao Y, Xu H, Liu C and Chen B: Targeted inhibition of ferroptosis in bone marrow mesenchymal stem cells by engineered exosomes alleviates bone loss in smoking-related osteoporosis. Mater Today Bio. 31:1015012025. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang D, Xiao W, Liu C, Wang Z, Liu Y, Yu Y, Jian C and Yu A: Exosomes derived from adipose stem cells enhance bone fracture healing via the activation of the Wnt3a/β-catenin signaling pathway in rats with type 2 diabetes mellitus. Int J Mol Sci. 24:48522023. View Article : Google Scholar | |
|
Sun W, Qu S, Ji M, Sun Y and Hu B: BMP-7 modified exosomes derived from synovial mesenchymal stem cells attenuate osteoarthritis by M2 polarization of macrophages. Heliyon. 9:e199342023. View Article : Google Scholar : PubMed/NCBI | |
|
Li X, Fang S, Wang S, Xie Y, Xia Y, Wang P, Hao Z, Xu S and Zhang YJ: Hypoxia preconditioning of adipose stem cell-derived exosomes loaded in gelatin methacryloyl (GelMA) promote type H angiogenesis and osteoporotic fracture repair. Nanobiotechnology. 22:1122024. View Article : Google Scholar | |
|
Lee AE, Choi JG, Shi SH, He P, Zhang QZ and Le AD: DPSC-derived extracellular vesicles promote rat jawbone regeneration. J Dent Res. 102:313–321. 2023. View Article : Google Scholar | |
|
Luo D, Xie W, He X, Zhou X, Ye P and Wang P: Exosomal miR-590-3p derived from bone marrow mesenchymal stem cells promotes osteoblast differentiation and osteogenesis by targeting TGFBR1. In Vitro Cell Dev Biol Anim. 61:46–58. 2025. View Article : Google Scholar | |
|
Zhang Y, Cao X, Li P, Fan Y, Zhang L, Ma X, Sun R, Liu Y and Li W: microRNA-935-modified bone marrow mesenchymal stem cells-derived exosomes enhance osteoblast proliferation and differentiation in osteoporotic rats. Life Sci. 272:1192042021. View Article : Google Scholar : PubMed/NCBI | |
|
Marini F, Giusti F, Palmini G and Brandi ML: Role of Wnt signaling and sclerostin in bone and as therapeutic targets in skeletal disorders. Osteoporos Int. 34:213–238. 2023. View Article : Google Scholar | |
|
Komori T: Bone development by Hedgehog and Wnt signaling, Runx2, and Sp7. J Bone Miner Metab. 43:33–38. 2025. View Article : Google Scholar | |
|
Samman WA, Mosalam EM, Saif DS, Abdallah MS, Zidan AA, Sallam AS, Abdelsattar S, Khalil FO, Elashkar AE, Mohamed SM, et al: Deciphering the role of Wnt/β-catenin and miR-214 in knee osteoarthritis: Molecular and clinical insights. Front Pharmacol. 16:15076932025. View Article : Google Scholar | |
|
Danz JC and Degen M: Selective modulation of the bone remodeling regulatory system through orthodontic tooth movement-a review. Front Oral Health. 6:14727112025. View Article : Google Scholar : PubMed/NCBI | |
|
Coombs CV, Greeves JP, Young CD, Irving AS, Eisenhauer A, Kolevica A, Heuser A, Tang JCY, Fraser WD and O'Leary TJ: The effect of calcium supplementation on bone calcium balance and calcium and bone metabolism during load carriage in women: A randomized controlled crossover trial. J Bone Miner Res. 13:zjaf0042025. | |
|
Rummler M, Ziouti F, Snyder L, Zimmermann EA, Lynch M, Donnelly E, Wagermaier W, Jundt F and Willie BM: Bone mechanical properties were altered in a mouse model of multiple myeloma bone disease. Biomater Adv. 166:2140472025. View Article : Google Scholar | |
|
Cai G, Lu Y, Zhong W, Wang T, Li Y, Ruan X, Chen H, Sun L, Guan Z, Li G, et al: Piezo1-mediated M2 macrophage mechanotransduction enhances bone formation through secretion and activation of transforming growth factor-β1. Cell Prolif. 56:e134402023. View Article : Google Scholar | |
|
Zhang J, Tong Y, Liu Y, Lin M, Xiao Y and Liu C: Mechanical loading attenuated negative effects of nucleotide analogue reverse-transcriptase inhibitor TDF on bone repair via Wnt/β-catenin pathway. Bone. 161:1164492022. View Article : Google Scholar | |
|
Hiasa M, Endo I and Matsumoto T: Bone-fat linkage via interleukin-11 in response to mechanical loading. J Bone Miner Metab. 42:447–454. 2024. View Article : Google Scholar : PubMed/NCBI | |
|
Bullock WA, Pavalko FM and Robling AG: Osteocytes and mechanical loading: The Wnt connection. Orthod Craniofac Res. 22(Suppl 1): S175–S179. 2019. View Article : Google Scholar | |
|
Simic MK, Mohanty ST, Xiao Y, Cheng TL, Taylor VE, Charlat O, Croucher PI and McDonald MM: Multi-Targeting DKK1 and LRP6 prevents bone loss and improves fracture resistance in multiple myeloma. J Bone Miner Res. 38:814–828. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Xun J, Li C, Liu M, Mei Y, Zhou Q, Wu B, Xie F, Liu Y and Dai R: Serum exosomes from young rats improve the reduced osteogenic differentiation of BMSCs in aged rats with osteoporosis after fatigue loading in vivo. Stem Cell Res Ther. 12:4242021. View Article : Google Scholar : PubMed/NCBI | |
|
Qi J, Zhang R and Wang Y: Exosomal miR-21-5p derived from bone marrow mesenchymal stem cells promote osteosarcoma cell proliferation and invasion by targeting PIK3R1. J Cell Mol Med. 25:11016–11030. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Liu W, Li L, Rong Y, Qian D, Chen J, Zhou Z, Luo Y, Jiang D, Cheng L, Zhao S, et al: Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126. Acta Biomater. 103:196–212. 2020. View Article : Google Scholar | |
|
Neogi T and Colloca L: Placebo effects in osteoarthritis: Implications for treatment and drug development. Nat Rev Rheumatol. 19:613–626. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Olansen J, Dyke JP and Aaron RK: Is osteoarthritis a vascular disease? Front Biosci (Landmark Ed). 29:1132024. View Article : Google Scholar : PubMed/NCBI | |
|
Zaussinger M, Schwaiger K, Schwarzbauer J, Bachleitner K, Holzbauer M, Ehebruster G and Schmidt M: Three-dimensional planning for vascularized bone grafts: Implementation and surgical application for complex bone reconstruction in the hand and forearm. J Clin Med. 14:4402025. View Article : Google Scholar : PubMed/NCBI | |
|
Song LL, Tang YP, Qu YQ, Yun YX, Zhang RL, Wang CR, Wong VKW, Wang HM, Liu MH, Qu LQ, et al: Exosomal delivery of rapamycin modulates Blood-brain barrier penetration and VEGF axis in glioblastoma. J Control Release. 381:1136052025. View Article : Google Scholar : PubMed/NCBI | |
|
Anderson JD, Johansson HJ, Graham CS, Vesterlund M, Pham MT, Bramlett CS, Montgomery EN, Mellema MS, Bardini RL, Contreras Z, et al: Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear Factor-KappaB signaling. Stem Cells. 34:601–613. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Vyas KS, Kaufman J, Munavalli GS, Robertson K, Behfar A and Wyles SP: Exosomes: The latest in regenerative aesthetics. Regen Med. 18:181–194. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Shen K, Duan A, Cheng J, Yuan T, Zhou J, Song H, Chen Z, Wan B, Liu J, Zhang X, et al: Exosomes derived from hypoxia preconditioned mesenchymal stem cells laden in a silk hydrogel promote cartilage regeneration via the miR-205-5p/PTEN/AKT pathway. Acta Biomater. 143:173–188. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Wang Y, Kong Y, Du J, Qi L, Liu M, Xie S, Hao J, Li M, Cao S, Cui H, et al: Injection of human umbilical cord mesenchymal stem cells exosomes for the treatment of knee osteoarthritis: From preclinical to clinical research. J Transl Med. 23:6412025. View Article : Google Scholar : PubMed/NCBI | |
|
Rajabloo Y, Al-Asady AM, Avan A, Khazaei M, Ryzhikov M and Hassanian SM: Unlocking therapeutic potential: Mesenchymal stem Cells-derived exosomes in IUA treatment, current status and perspectives. Curr Pharm Des. 31:1663–1672. 2025. View Article : Google Scholar : PubMed/NCBI | |
|
Infante A and Rodríguez CI: Osteogenesis and aging: Lessons from mesenchymal stem cells. Stem Cell Res Ther. 9:2442018. View Article : Google Scholar : PubMed/NCBI | |
|
Liu S, Liu D, Chen C, Hamamura K, Moshaverinia A, Yang R, Liu Y, Jin Y and Shi S: MSC transplantation improves osteopenia via epigenetic regulation of Notch signaling in lupus. Cell Metab. 22:606–618. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang L, Jiao G, Ren S, Zhang X, Li C, Wu W, Wang H, Liu H, Zhou H and Chen Y: Exosomes from bone marrow mes enchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion. Stem Cell Res Ther. 11:382020. View Article : Google Scholar | |
|
Chen S, Tang Y, Liu Y, Zhang P, Lv L, Zhang X, Jia L and Zhou Y: Exosomes derived from miR-375-overexpressing human adipose mesenchymal stem cells promote bone regeneration. Cell Prolif. 52:e126692019. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou QF, Cai YZ and Lin XJ: The dual character of exosomes in osteoarthritis: Antagonists and therapeutic agents. Acta Biomater. 105:15–25. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Chen P, Zheng L, Wang Y, Tao M, Xie Z, Xia C, Gu C, Chen J, Qiu P, Mei S, et al: Desktop-stereolithography 3D printing of a radially oriented extracellular matrix/mesenchymal stem cell exosome bioink for osteochondral defect regeneration. Theranostics. 9:2439–2459. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Liu X, Yang Y, Li Y, Niu X, Zhao B, Wang Y, Bao C, Xie Z, Lin Q and Zhu L: Integration of stem cell-derived exosomes with in situ hydrogel glue as a promising tissue patch for articular cartilage regeneration. Nanoscale. 9:4430–4438. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Li W, Liu Y, Zhang P, Tang Y, Zhou M, Jiang W, Zhang X, Wu G and Zhou Y: Tissue-engineered bone immobilized with human adipose stem cells-derived exosomes promotes bone regeneration. ACS Appl Mater Interfaces. 10:5240–5254. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Ni Z, Zhou S, Li S, Kuang L, Chen H, Luo X, Ouyang J, He M, Du X and Chen L: Exosomes: Roles and therapeutic potential in osteoarthritis. Bone Res. 8:252020. View Article : Google Scholar : PubMed/NCBI | |
|
Rudiansyah M, El-Sehrawy AA, Ahmad I, Terefe EM, Abdelbasset WK, Bokov DO, Salazar A, Rizaev JA, Muthanna FMS and Shalaby MN: Osteoporosis treatment by mesenchymal stromal/stem cells and their exosomes: Emphasis on signaling pathways and mechanisms. Life Sci. 306:1207172022. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang L, Wang Q, Su H and Cheng J: Exosomes from adipose derived mesenchymal stem cells alleviate diabetic osteoporosis in rats through suppressing NLRP3 inflammasome activation in osteoclasts. J Biosci Bioeng. 131:671–678. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Liang Y, Xu X, Li X, Xiong J, Li B, Duan L, Wang D and Xia J: Chondrocyte-targeted microRNA delivery by engineered exosomes toward a cell-free osteoarthritis therapy. ACS Appl Mater Interfaces. 12:36938–36947. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
He L, He T, Xing J, Zhou Q, Fan L, Liu C, Chen Y, Wu D, Tian Z, Liu B and Rong L: Bone marrow mesenchymal stem cell-derived exosomes protect cartilage damage and relieveknee osteoarthritis pain in a rat model of osteoarthritis. Stem Cell Res Ther. 11:2762020. View Article : Google Scholar | |
|
Lu M, Lou A, Gao J, Li S, He L, Fan W and Zhao L: Quercetin-primed MSC exosomes synergistically attenuate osteoarthritis progression. J Orthop Surg Res. 20:3732025. View Article : Google Scholar : PubMed/NCBI | |
|
Chen Q, Lin Y, Li W, Zhang X, Asahara H, Zheng M, Zhang YC, Xie T, Sun LY, Chang J, et al: Engineered cartilage-targeting extracellular vesicles deliver anti-inflammatory RNAi therapy for osteoarthritis treatment. Sci Transl Med. 17:eabn02592025. | |
|
Zhang Y, Kirkland JL, Chen W, Qin L, Chen X, Yang H, Zhang T, Lin JH, Zhang ZM, Cao X, et al: Systemically administered exosomes derived from mesenchymal stem cells mitigate bone loss by targeting osteogenesis in postmenopausal osteoporosis. Nat Commun. 15:32182024. | |
|
Yoo J, Lee SK, Lim M, Sheen D, Choi EH and Kim SA: Exosomal amyloid A and lymphatic vessel endothelial hyaluronic acid receptor-1 proteins are associated with disease activity in rheumatoid arthritis. Arthritis Res Ther. 19:1192017. View Article : Google Scholar : PubMed/NCBI | |
|
Zhao Y and Xu J: Synovial fluid-derived exosomal lncRNA PCGEM1 as biomarker for the different stages of osteoarthritis. Int Orthop. 42:2865–2872. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Y, Cai F, Liu J, Chang H, Liu L, Yang A and Liu X: Transfer RNA-derived fragments as potential exosome tRNA-derived fragment biomarkers for osteoporosis. Int J Rheum Dis. 21:1659–1669. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Wang L, Wang C, Jia X and Yu J: Circulating exosomal miR-17 inhibits the induction of regulatory T cells via suppressing TGFBR II expression in rheumatoid arthritis. Cell Physiol Biochem. 50:1754–1763. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Xia B, Di Chen, Zhang J, Hu S, Jin H and Tong P: Osteoarthritis pathogenesis: A review of molecular mechanisms. Calcif Tissue Int. 95:495–505. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang E, Chen L, Wang YF, Smith JR, Yamamoto HE and Johnson SK: Cryopreservation of exosomes with enhanced bioactivity using liquid nitrogen and novel cryoprotectants. Nat Commun. 15:1238–1256. 2024. | |
|
Stevenson J; Medical advisory council of the British Menopause Society: Prevention and treatment of osteoporosis in women. Post Reprod Health. 29:11–14. 2023. View Article : Google Scholar : | |
|
Galanis A, Dimopoulou S, Karampinas P, Vavourakis M, Papagrigorakis E, Sakellariou E, Karampitianis S, Zachariou D, Theodora M, Antsaklis P, et al: The correlation between transient osteoporosis of the hip and pregnancy: A review. Medicine (Baltimore). 102:e354752023. View Article : Google Scholar : PubMed/NCBI | |
|
Gehrke B, Alves Coelho MC, Brasil d'Alva C and Madeira M: Long-term consequences of osteoporosis therapy with bisphosphonates. Arch Endocrinol Metab. 68:e2203342023. View Article : Google Scholar : PubMed/NCBI | |
|
Yu S, Chen H and Gao B: Potential therapeutic effects of exosomes in regenerative endodontics. Arch Oral Biol. 120:1049462020. View Article : Google Scholar : PubMed/NCBI | |
|
Munagala R, Aqil F, Jeyabalan J and Gupta RC: Bovine Milk-derived exosomes for drug delivery. Cancer Lett. 371:48–61. 2016. View Article : Google Scholar : | |
|
Zhang S, Wong KL, Ren X, Teo KYW, Afizah H, Choo ABH, Lai RC, Lim SK, Hui JHP and Toh WS: Mesenchymal stem cell exosomes promote functional osteochondral repair in a clinically relevant porcine model. Am J Sports Med. 50:788–800. 2022. View Article : Google Scholar : PubMed/NCBI |
