Abstract

Osteoarthritis (OA) is a relatively common chronic degenerative disease of joints that was originally considered an imbalance between mechanical loads and tissue repair. Emerging evidence indicates that exercise confers protection not merely through mechanical loading, but also by acting as a systemic regulator of RNA metabolism. This modulation mainly happens by regulating RNA–RNA-binding protein interaction networks that can regulate joint homeostasis and delay the OA process. This article is a review of current understanding of how physical activity alters networks of RNA–RNA-binding proteins (RBPs) in different joint-related tissues, such as cartilage, synovium, skeletal muscle, and systemic circulation, and changes the metabolic and inflammatory pathways necessary for joint health. The article will examine molecular mechanisms by which exercise induces RNA metabolism reprogramming and protection from OA. It also studies the promising prospects of RNA–RBP networks in early detection of OA and targeting innovative treatment strategies. By combining what we know about RNA–RBP interaction with exercise physiology, this overview could clear the way to personalized exercise interventions and novel RNA-targeted therapies for OA.

Exercise rewires the RNA–RBP interactome to protect against osteoarthritis. Mechanical loading signals (e.g., Piezo1) initiate a protective signaling cascade that remodels RNA–RBP networks across joint tissues. This systemic modulation orchestrates three key protective mechanisms: enhancing matrix anabolism, suppressing synovial inflammation, and inhibiting chondrocyte senescence, collectively restoring joint homeostasis.

1 Introduction

Osteoarthritis (OA) is a common joint degenerative disease that is a substantial cause of disability for millions of people. Both individuals and healthcare systems face a substantial disease burden (Zeng et al., 2025). Epidemiological data from global burden of disease studies show an increasing trend in the prevalence, incidence, and disability-adjusted life years of osteoarthritis during the past 3 decades, and it is projected to increase in the coming decades (Ding et al., 2024; Wang and Ye, 2024; Xie et al., 2025; Zhou J. et al., 2025). The burden of disease falls on older people and on areas with higher socio-demographic indices, driving the need for efficient prevention and control measures (Li Z. et al., 2025; Zeng et al., 2025). Women and middle-aged and older people are more prone to the disease, making the need for targeted interventions urgent (Ding et al., 2024; Sun et al., 2025). Although OA has a significant impact on quality of life and physical functioning, the current therapeutic strategies are mainly aimed at reducing symptoms, providing pain relief, and functional enhancement. However, these interventions are of low efficacy and incapable of inhibiting or improving the progression of the disease (Chen X. et al., 2024; Kim et al., 2025). The traditional pharmacologic agents, including NSAIDs, duloxetine, intra-articular injections, and so forth, have had little benefit in the long run and are accompanied by safety issues (Cao et al., 2020). Regenerative medicine methods such as mesenchymal stem cells and autologous conditioned serum have shown potential in preliminary clinical trials, but further research is needed to confirm (Chen X. et al., 2024; Jeyaraman et al., 2024). The development of disease-modifying osteoarthritis drugs remains an unmet need, as is research on targeting inflammation-driven, bone-driven, and cartilage-driven endotypes of OA (Makaram and Simpson, 2023; Oo, 2024; Rodriguez-Merchan, 2023). Non-pharmacological interventions, particularly exercise, have become a pillar of OA treatment. Exercise therapy is widely recommended in clinical guidelines for knee and hip OA and is helpful in reducing pain and improving physical function and quality of life (Lawford et al., 2024). Exercise is the only intervention that may have disease-modifying effects via its influence on joint tissue homeostasis and metabolic regulation (Deng et al., 2023; Du et al., 2024). The beneficial effects from exercise are not only from mechanical load but also from molecules and cells, by modulating inflammatory cytokines, and improving cartilage metabolism and regulation of subchondral bone remodeling (Du et al., 2024; Ma et al., 2024). Traditional Chinese exercises such as Tai Chi and Qigong can also help with the symptoms, tissue healing, and immune modulation, reducing joint inflammation (Du et al., 2024; Zhou et al., 2024). Even though the role of exercise is acknowledged, the exact molecular pathway by which exercise provides protection against joint disease has not been fully elucidated. A critical gap remains in understanding how macroscopic mechanical signals from exercise are translated into precise molecular outcomes. While traditional studies focus on signaling pathways, they often overlook the speed and complexity of cellular adaptation. This is where RNA–RBP networks become crucial. Unlike slow transcriptional changes, RBPs provide rapid “post-transcriptional” control, allowing joint cells (like chondrocytes) to instantly adjust their RNA stability and protein synthesis during the metabolic stress of exercise. Therefore, focusing on the RNA–RBP axis offers a unique and necessary rationale: it explains the “fast-response” mechanism that connects physical movement to long-term tissue repair. In the past, some studies found that RNA molecules, along with RBPs, also appear as dynamic regulators that respond to exercise produced by some mechanical or biochemical stimulations. RBPs serve as essential post-transcriptional regulators, orchestrating RNA splicing, stability, localization, and translation to ensure precise gene expression control (Flamand and Meyer, 2024; Kelaini et al., 2021). Exercise-induced modulation of RNA–mRNA localization, stability, and translation is a novel systemic reprogramming mode that may underlie the disease-modifying benefit of exercise in OA. This kind of all-round understanding is likely to find molecular targets for translation medicine, and on this basis, to develop new therapies that mimic or improve upon the protective effects of exercise in OA while maintaining joint integrity, reducing inflammation, and allowing healing (Wu et al., 2025). Therefore, this review hopes to integrate the current knowledge on the epidemiological burden of OA, the clinical efficiency of exercise as a disease-modifying intervention, and the molecular mediators involving the RNA–RBP network. We will study the molecular mechanism by which exercise regulates RNA metabolism to maintain joint tissue homeostasis and explore the translation prospects of this mechanism for OA treatment.

2 Basic RNA–RBP regulatory network in joint homeostasis2.1 RNA diversity in joint tissues

There are many RNA species in joint tissues, and these species are responsible for maintaining joint homeostasis and mediating the pathogenesis of OA and RA. Among the RNAs, circular RNAs (circRNAs) have emerged as pivotal regulators to maintain the stability of the cartilage. Protective circRNAs help maintain the stability of the cartilage matrix by governing the synthesis of proteoglycans, which are critical components of the extracellular matrix (ECM) that give cartilage its load-bearing capacity. For example, some specific circRNAs have been found to regulate the expression of genes related to proteoglycan synthesis, so as to maintain the stability of the cartilage matrix and inhibit the degradation characteristics of OA (Ghanekar and Sadasivam, 2022). These circRNAs function as molecular “sponges” for miRNAs and act as scaffolds for RNA-binding proteins (RBPs) to modulate post-transcriptional modifications.

Another class of regulatory RNAs involved in joint inflammation and tissue remodeling is long non-coding RNAs (lncRNAs). Certain lncRNAs specifically modulate synovial inflammation by targeting inflammatory signaling pathways in fibroblast-like synoviocytes (FLSs), the main effector cells in synovitis. For instance, the lncRNA HAFML binds to the RBP HuR to stabilize mRNAs coding for proteins involved in FLS migration and invasion, both key aspects of joint destruction in rheumatoid arthritis (RA) (Xu et al., 2023). Furthermore, lncRNAs such as PVT1 work as competing endogenous RNAs (ceRNAs), whereby they sponge miRNAs like miR-140 and promote the expression of matrix-degrading enzymes (such as ADAMTS5 and MMP13) in chondrocytes to accelerate the degradation of the ECM in OA (Yao et al., 2022). These findings demonstrate that lncRNAs can participate in the organization and modulation of inflammatory reactions and matrix reconstruction processes in joint tissues.

MicroRNAs (miRNAs) are critical post-transcriptional regulators that determine chondrocyte fate, including survival, apoptosis, proliferation, and differentiation. Key miRNAs that regulate chondrocyte viability and balance the anabolic and catabolic activities of the cartilage have been identified. Dysregulation of these miRNAs results in enhanced chondrocyte apoptosis and impaired regeneration, which facilitates the progression of OA (Gu et al., 2023). The mutual influence among miRNAs, lncRNAs, circRNAs, and other RNA species is established in a complex regulatory network and jointly regulates gene expression.

Emerging research reveals that certain circRNAs and mRNAs can encode short functional peptides, thereby expanding the functional repertoire of non-coding RNAs. These peptides are increasingly recognized for their roles in modulating cellular metabolism and signaling pathways essential for joint homeostasis (Zhang C. et al., 2025)

Advances in single-cell RNA sequencing (scRNA-seq) and multi-omics technologies have significantly enhanced our understanding of cellular and molecular heterogeneity within joint tissues. These technologies enable the characterization of unique transcriptomic signatures across diverse cell types, detailing the expression patterns of various RNA species. For instance, scRNA-seq studies have identified several subsets of synovial macrophages and fibroblasts with distinct RNA expression signatures that are involved in inflammation and tissue remodeling in OA and RA (Laouteouet et al., 2025; Zhang et al., 2023). Moreover, integrative analysis between chromatin accessibility and transcriptomics has identified a regulatory network controlling joint cell RNA expression (Li H. et al., 2025).

Joint tissues harbor a diverse array of RNA species that collectively maintain joint integrity and promote OA pathogenesis. As summarized in Table 1, distinct RNA classes exert specialized regulatory functions: circRNAs modulate ECM metabolism by promoting synthesis or inhibiting degradation; lncRNAs regulate synovial pro-inflammatory responses and enhance target mRNA stability; and miRNAs govern the activity and polarization of chondrocytes and macrophages, while long non-coding RNAs may help modulate the synovium’s pro-inflammation response. Some can enhance the stability of target mRNA molecules and promote ECM formation; Finally, microRNAs have the functions of governing the activity and polarization of chondrocytes and macrophages, respectively, to achieve a moderate coexistence of the synthesizing and removing processes for the joint. There is some evidence that some circRNAs and mRNAs can code for functional peptides, which may further expand the scope of RNA regulation in joint biochemistry. These various types of RNAs interact with each other all the time and form networks that maintain the health of the joint and enable the RNA to respond to pathogenic stimuli like inflammation or mechanical stress (Kong et al., 2021).

RNA typeSpecific molecular exampleCore functionReferenceCircular RNAs (circRNAs)circPRKCH, circ-slain2, and hsa_circ_0000448Regulate cartilage ECM synthesis and degradation, inhibit chondrocyte apoptosis, participate in inflammatory signaling pathways, and act as miRNA spongesHu et al. (2019); Pan et al. (2023); Que et al. (2022)Long non-coding RNAs (lncRNAs)HAFML, PVT1, WDR11-AS1, and MIR31HGRegulate synovial inflammation, stabilize target mRNA expression, promote ECM synthesis, and inhibit AKT inflammatory signaling pathwayCao L. et al. (2021); Huang et al. (2023); Xu et al. (2023); Yao et al. (2022)MicroRNAs (miRNAs)miR-140, miR-221-3p, miR-145, and miR-27a-3pRegulate chondrocyte proliferation/apoptosis, modulate macrophage polarization, and promote bone anabolic metabolismQue et al. (2022); Quero et al. (2019); Yao et al. (2022); Zhang B. et al. (2025)circRNAs/mRNAs encoding peptidesUnknown (functional peptides)Regulate chondrocyte metabolism, participate in cellular signaling pathways, and maintain joint tissue homeostasisZhang M. et al. (2025)

Key RNA types in joint tissues, their core regulatory functions, and corresponding references.

This table summarizes the main RNA species involved in joint homeostasis and osteoarthritis pathogenesis, including their representative molecular examples, critical regulatory roles in joint tissues such as cartilage and synovium, and relevant references. The regulatory functions listed are primarily derived from in vitro and in vivo experimental evidence in the cited studies.

To conclude, RNA diversity of joint tissue includes many protective circRNAs that guard cartilage ECM, inflammation-regulating lncRNAs in the synovium, miRNAs deciding the fate of chondrocytes, and coding circRNAs/mRNAs creating functional peptides. These different types of RNA interact with each other via RNA–RBP and epigenetic regulation, which regulates their joint homeostasis and pathologic processes in tissues. To comprehend such complex RNA nets is expected to provide direction for targeted, effective interventions to block or minimize joint diseases such as OA and RA.

2.2 Key RNA-binding proteins and their functions

RNA-binding proteins (RBPs) are central orchestrators of post-transcriptional gene regulation, governing essential processes such as alternative splicing, mRNA stability, subcellular localization, and translational initiation (Zigdon et al., 2024). In the context of osteoarthritis (OA), a degenerative joint disease characterized by progressive cartilage loss and chronic inflammation, RBPs serve as indispensable regulators of chondrocyte phenotypes and the maintenance of cartilage homeostasis. Notably, several specific RBPs have emerged as key mediators that modulate RNA metabolism, thereby profoundly influencing the pathophysiology and progression of OA.

2.3 Heterogeneous nuclear ribonucleoprotein family: regulation of RNA splicing, stability, and nucleocytoplasmic transport affecting chondrocyte stress response

The heterogeneous nuclear ribonucleoprotein (HNRNP) family is a group of RBPs that primarily participate in the processing of pre-mRNA, including pre-mRNA alternative splicing, mRNA stability, nuclear–cytoplasmic transport, etc. They bind to heterogeneous nuclear RNA and determine the functional fate and metabolic outcome of these RNAs. In OA, the members of the HNRNP family alter the response of chondrocytes to cell stress and inflammation, which are the main causes of cartilage damage. HNRNPD promotes chondrocyte senescence and OA progression through upregulating FOXM1 (Jiang et al., 2024), a transcription factor implicated in mitochondrial dysfunction and cellular aging. Similarly, HNRNPs may regulate the stability and translation of mRNAs encoding inflammatory mediator proteins and extracellular matrix proteins and thus modulate chondrocyte survival and maintain the integrity of the cartilage matrix (Wang H. et al., 2023; Zhang S. et al., 2024). Dynamic regulation of RNA splicing by HNRNPs may produce protein isoforms that either prevent or worsen cartilage injury. Moreover, HNRNPs are a part of stress granules and of RNA–protein complexes that are involved in the regulation of the cellular adaptation to oxidative and inflammatory stress, common in OA pathogenesis (Goswami et al., 2023). Therefore, the HNRNP family serves as a pivotal nexus between RNA metabolism and chondrocyte stress responses and influences the course and progression of OA.

2.4 RBMS proteins: involvement in mRNA stability and translational control linked to cartilage matrix protein expression

The RNA-binding motif, single-stranded interacting (RBMS) protein family, constitutes another critical group of regulators governing mRNA stability and translation. RBMS proteins bind to specific sequences or structures of target mRNAs to modulate their half-life and translational efficiency. This regulatory capacity is specifically targeted to the expression of cartilage extracellular matrix proteins, such as collagen and aggrecan, which are required for the formation and maintenance of cartilage. RBMS-mediated dysregulation of RBMS-mediated mRNA stability leads to dysregulated synthesis of ECM proteins, causing the cartilage degradation seen in OA. For example, RBMS proteins may stabilize the mRNAs encoding anabolic factors and destabilize the mRNAs encoding matrix-degrading enzymes, thereby achieving fine regulation of the balance between cartilage anabolism and catabolism. Although direct studies of RBMS proteins in OA are scarce, the known functions of these proteins in mRNA regulation and evidence from related tissues indicate that they are important for maintaining the homeostasis of cartilage by post-transcriptional regulation of matrix protein expression (Eraso et al., 2023; Yoon et al., 2022). Furthermore, RBMS proteins may interact with long non-coding RNAs (lncRNAs) and microRNAs, adding a layer of complexity to the post-transcriptional regulation of chondrocyte gene expression in OA.

2.5 IGF2BP family: modulation of mRNA localization and translation involved in cellular metabolism and inflammatory responses

Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) are a group of RBPs that orchestrate mRNA localization, stability, and translation, thereby modulating cellular metabolism and inflammatory pathways (Wang et al., 2021). IGF2BPs bind to specific regions within the 5′ and 3′ untranslated regions of target mRNAs to regulate their localization, stability, and translation efficiency. In the setting of OA, the IGF2BP family of members was shown to regulate the transcription of metabolic genes in chondrocytes as well as inflammatory signaling genes. For instance, IGF2BP2 is associated with adipogenesis and metabolic regulation processes, which intersect with OA pathogenesis through systemic and local metabolic alterations (Zhang P. et al., 2022). In addition, dysregulated IGF2BP expression may also impact the stability and translation of mRNAs encoding cytokines and matrix metalloproteinases to alter the inflammatory environment and matrix remodeling in osteoarthritic cartilage. Studies have also shown that IGF2BPs are involved in RNA methylation pathways and are able to interact with circular RNAs, which have also been shown to be regulatory RNAs in OA (Shi and Zhao, 2025; Singh et al., 2025). The IGF2BP family all function as key post-transcriptional regulators, regarding mRNAs and metabolic and inflammatory processes that contribute to the progression of osteoarthritis.

To systematically categorize the molecular targets and specific regulatory effects of these key RBPs in OA, their distinct mechanisms are summarized in Table 2. In addition to the HNRNP, RBMS, and IGF2BP families, other important RBPs, including HNRNP, RBMS, PABPC1, PUM1, PUM2, SND1, and YTHDF3, interact with target mRNAs to directly modulate cartilage integrity, chondrocyte survival, and synovial inflammatory responses. This comprehensive overview highlights the functional complexity of individual RBPs and underscores the depth of the RBP regulatory network in OA.

RBP family/ProteinSpecific membersMolecular targets (RNAs/mRNAs)Regulatory effects in OA pathogenesisReferenceHNRNP familyHNRNPD (AUF1)FOXM1 mRNAPromotes chondrocyte senescence by upregulating FOXM1; induces mitochondrial dysfunction and cellular aging; accelerates OA progressionJiang et al. (2024)HNRNPA1TRIM37 mRNA and TRAF6-related mRNAsStabilizes TRIM37 mRNA; mediates TRAF6 ubiquitination to alleviate cartilage inflammation and degradationDeng H. et al. (2025)HNRNPQAutophagy-related mRNAs (ATG5 included)Regulates autophagosome biogenesis; mutations impair autophagy, contributing to age-related joint tissue dysfunctionIshtayeh et al. (2023)RBMS proteinsRBMS1/2/3Collagen, aggrecan, and matrix-degrading enzyme mRNAsStabilizes mRNAs of anabolic ECM proteins; destabilizes mRNAs of catabolic enzymes (MMPs/ADAMTS); balances cartilage synthesis and breakdownEraso et al. (2023);Yoon et al. (2022)IGF2BP familyIGF2BP2mRNAs of cytokines, MMPs, and adipogenesis-related genesModulates mRNA localization and translation; regulates chondrocyte metabolism, inflammatory signaling, and systemic metabolic cross talk in OAShi and Zhao (2025); Singh et al. (2025); Zhang P. et al. (2022)Other key RBPsPABPC1SOX9 mRNA (regulated by lncRNA WDR11-AS1)Directly binds and stabilizes SOX9 mRNA; increases ECM synthesis (collagen/aggrecan); counteracts OA-related cartilage degenerationHuang et al. (2023)PUM1TLR4 mRNASuppresses TLR4 mRNA translation; attenuates NF-κB signaling and cellular senescence; protects cartilage integrityLv G. et al. (2022);Yoon et al. (2022)PUM2FOXO3 mRNABinds to 3′-UTR of FOXO3 mRNA; reduces FOXO3 expression; promotes IL-1β-induced chondrocyte apoptosis and ROS generationWang D. et al. (2024)SND1HSPA5 mRNADestabilizes HSPA5 mRNA; decreases GPX4 expression; induces chondrocyte ferroptosis and cartilage damageLv M. et al. (2022)YTHDF3LRRC17 mRNA (m6A-modified)Stabilizes m6A-mediated LRRC17 mRNA; activates STAT1 signaling; increases ROS and mitochondrial dysfunction; accelerates chondrocyte senescenceTang et al. (2025)

Key RNA-binding proteins (RBPs) in osteoarthritis: families, molecular targets, regulatory effects, and corresponding references.

This table summarizes core RBPs involved in osteoarthritis pathogenesis, covering major RBPs, families, and critical individual members. It includes their direct RNA/mRNA, targets, specific regulatory effects on joint tissues such as cartilage and synovium, and relevant supporting references. The regulatory effects described are primarily based on experimental evidence from in vitro cell studies and in vivo animal models of osteoarthritis, reflecting the functional diversity of RBPs in modulating RNA metabolism and joint homeostasis.

2.6 Synergistic roles of RNA–RBP networks in joint homeostasis

RNA-binding proteins (RBPs) form complex regulatory networks with the target RNA and jointly maintain the homeostasis of the whole organism by precisely tuning gene expression at the post-transcriptional level. A central component of this regulation involves governing the balance between the synthesis and degradation of the cartilage extracellular matrix (ECM). RBPs selectively bind to target transcripts bearing the instruction codes for making the ECM, as well as for creating matrix-degrading enzymes, thereby dictating mRNA stability and translation efficiency to sustain this critical balance (Shao et al., 2020). For example, poly(A)-binding protein cytoplasmic 1 (PABPC1) binds to SOX9 mRNA and encodes a master transcription factor for ECM synthesis. This interaction is modulated by the long non-coding RNA (lncRNA) WDR11-AS1. This stabilization of SOX9 mRNA increases ECM anabolism, thereby inhibiting osteoarthritic cartilage erosion (Huang et al., 2023). In contrast, inflammatory signals increase RBPs, such as ALKBH5, and via m6A RNA demethylation, modulating the stability of RUNX2 mRNA. This transcription factor leads to the expression of matrix metalloproteinases and ADAMTS enzymes, which in turn break down ECM and accelerate osteoarthritis (OA) progression (Lei et al., 2024; Nie et al., 2025). Collectively, RNA–RBP complexes act as molecular rheostats, dynamically governing the anabolic and catabolic processes of cartilage to maintain ECM homeostasis.

Beyond their role in cartilage matrix regulation, RBP–RNA interaction networks are critically important in determining whether inflammation is initiated within the synovium. Dysfunctional chondrocyte-derived exosomes enriched in lncRNAs such as OANCT bind to RNA demethylases such as FTO, influencing the stability of mRNAs encoding PIK3R5 that activate the PI3K/AKT/mTOR pathway, thus promoting macrophage polarization to a pro-inflammatory M1 type and aggravating synovitis in OA (Lv et G. al., 2022; Zhang et al., 2020). Furthermore, RBPs such as HuR stabilize mRNAs encoding proteins involved in migration and invasion of the fibroblast-like synoviocytes, contributing to synovial hyperplasia and inflammation of rheumatoid arthritis, which may be related to the synovitis of osteoarthritis (Xu et al., 2023). It shows that RNA–RBP complexes can be fine-tuned under certain circumstances to play a role in synovial immune response and inflammatory thresholds. Although these mechanisms are indispensable for maintaining joint homeostasis, they may also drive pathological disease progression (Yu et al., 2025; Zhou Y. et al., 2025).

Aging and cellular senescence add another layer of complexity to joint homeostasis by altering RNA–RBP interactions that regulate the senescence-associated secretory phenotype. RBPs, such as the m6A reader YTHDF3, stabilize LRRC17 mRNA, which activates STAT1 signaling to induce chondrocyte senescence and increase ROS and mitochondrial dysfunction, causing a more severe osteoarthritis pathology (Tang et al., 2025). Similarly, RBPs such as PABPN1 and HNRNPQ, which regulate the expression of autophagy-related genes, also show dysfunctions due to mutations; these may result in reduced autophagosome biogenesis and cause age-related cellular dysfunction of joint tissue (Ishtayeh et al., 2023). The interplay between RBPs and non-coding RNAs in SASP regulation is an important aspect of the maintenance of joint tissue homeostasis in the course of aging and OA development.

RNA–RBP networks function synergistically to establish a complex regulatory environment in the joint tissue system, while balancing ECM synthesis and breakdown, regulating synovial inflammatory responses, and controlling cellular senescence and SASP. The disruption of these networks occurs in conditions such as OA, highlighting the possibility of therapeutic intervention by targeting the RNA–RBP interactions to reverse joint disequilibrium and halt progression of the disease (Cho et al., 2024; Guo et al., 2025; Sun et al., 2024; Suo et al., 2025). In the future, multiple RBPs can be profiled at the same time using more advanced techniques such as TRIBE-STAMP, and our understanding of the dynamic RNA–RBP interactions will also be increased in joint biology (Flamand and Meyer, 2024; Jin et al., 2024)

3 Exercise-induced multi-tissue RNA–RBP network reconstruction3.1 Exercise-mediated regulation of RNA–RBP networks across tissues

As a non-invasive and effective intervention, exercise can halt osteoarthritis progression by modulating RNA–RBP networks across various joint tissues (Jia et al., 2023). This systemic regulation is not only the mechanical sensation in the local cartilage, but also the crosstalk of tissue of muscle and bone, the internal anti-inflammatory activity of synovium, and the far-reaching regulation through circulating factors. Table 3 summarizes the regulatory effects from five aspects: mechanical sensing-triggered local responses of cartilage, bidirectional interaction of the muscle–bone axis, anti-inflammatory regulation of synovium, system-wide intercellular communication via exosomes, and epitranscriptomic modulation through RNA methylation (Lai et al., 2025; Wang H. et al., 2024; Zhang K. et al., 2025). Each of these aspects can exist with specific molecular mediators, including mechanosensitive channels, exosomal RNAs, and RNA-modifying enzymes, that in whole rewire RNA–RBP interactions to re-establish joint homeostasis (Chen L. et al., 2024; Esmaeili et al., 2021; Gao et al., 2022; Shang et al., 2021; Steinecker-Frohnwieser et al., 2023).

Regulatory dimensionTarget tissueCore regulatory mechanismsKey molecular mediatorsBiological effects in OA protectionReferenceLocal tissue response (mechanical sensing)Cartilage1. Piezo1 ion channel activation induces mechanosensitive circRNA expression
2. ceRNA (circRNA/lncRNA) sponges miRNAs to modulate RBP–mRNA interactions
3. Primary cilia-mediated signaling intersects with RNA–RBP networksPiezo1, circRNAs (Piezo1-associated), lncRNAs, miRNAs, PABPC1, SOX9, MMP3/13, and ADAMTS4/5- Enhances synthesis of proteoglycans and collagen
- Inhibits chondrocyte apoptosis and ECM degradation
- Regulates PI3K/AKT/NF-κB inflammatory pathwaysCheng et al. (2020); Ling et al. (2025); Zhou et Z. al. (2026)Muscle–bone axis cross talkSkeletal muscle + bone1. Exercise-induced myokines trigger exosomal RNA secretion
2. RBP-mediated post-transcriptional regulation of osteocalcin and bone anabolic factors
3. Bidirectional exosomal miRNA exchange between muscle and boneExosomal miRNAs (miR-34a, miR-27a-3p, miR-486-5p, and miR-222-3p), IGF2BP2, osteocalcin, and STAT3- Promotes bone anabolic responses and osteoblast differentiation
- Enhances muscle regeneration
- Alleviates osteosarcopenia-related joint instabilityWang B. et al. (2023); Wang et al. (2025); Zhang B. et al. (2025)Synovial anti-inflammatory regulationSynovium1. Induction of anti-inflammatory ncRNAs to suppress pro-inflammatory signaling
2. Modulation of RNA methylation (m6A) on inflammatory mediator mRNAs
3. RBP-regulated cytokine production in synovial macrophages/FLSsmiRNAs (miR-221-3p), lncRNAs (MIR31HG), RBPs (HuR/ELAVL1), TGM2 (m6A-modified), JAK3/STAT3, and AKT- Shifts macrophages from M1 to an anti-inflammatory phenotype
- Inhibits FLS migration and inflammatory molecule production
- Attenuates synovitis and synovial hyperplasiaCao L. et al. (2021); Lin et al. (2022); Quero et al. (2019); Wood et al. (2024)Systemic intercellular communicationSystemic circulation + joint cells1. Exercise remodels exosomal RNA cargo (circRNAs/miRNAs) for long-distance transport
2. Exosomal RNAs target host cell RBPs to rewire RNA–RBP networks
3. ADAR-mediated RNA editing optimizes RNA–RBP binding specificityExosomes, circRNAs (hsa_circ_0000448), miRNAs, RBPs (PUM1/PUM2, and HSPB1), ADARs, FOXO3, and COL5A1- Enhances chondrocyte survival and ECM homeostasis
- Inhibits pro-inflammatory pathways (TNF-α and NF-κB)
- Improves RNA metabolic reprogramming in joint cellsFu et al. (2024); Hu et al. (2019); Su et al. (2024)Epitranscriptomic regulationMultiple tissues (cartilage/synovium)1. Exercise modulates m6A methylation of circRNAs/mRNAs
2. m6A readers/writers (YTHDF1/2 and ALKBH5) regulate RBP–mRNA stabilitym6A-modified circRNAs (hsa_circ_0007259), m6A enzymes (ALKBH5 and YTHDF1/2), RUNX2, and SETD7 mRNA- Suppresses matrix-degrading enzymes (MMPs/ADAMTS)
- Inhibits chondrocyte autophagy suppression and inflammation
- Enhances RNA–RBP network specificityLi L. et al. (2025); Luo et al. (2023); Nie et al. (2025)

Exercise-induced RNA–RBP network regulation across multiple tissues: mechanisms, molecular mediators, and references.

This table summarizes the multi-dimensional regulatory roles of exercise in modulating RNA–RBP networks for osteoarthritis protection. It covers key regulatory dimensions, corresponding target tissues, core mechanisms, critical molecular mediators, biological effects, and relevant references. The included mechanisms integrate mechanical sensing, inter-tissue cross talk, inflammatory regulation, systemic communication, and epitranscriptomic modification, reflecting the systemic and coordinated characteristics of exercise-induced joint protection. All regulatory effects are supported by experimental evidence from in vitro cell studies, in vivo animal models, and partial clinical cohort data.

Importantly, these molecular pathways do not operate in isolation; rather, they function as an integrated network coupling local mechanical signals to distant biochemical responses to resist OA pathogenesis (Pérez-García et al., 2016; 2019; Li R. et al., 2022). As illustrated in Figure 1, we propose a global model in which exercise coordinately rewires RNA–RBP interactions across multiple tissues to restore joint homeostasis. The following sections will systematically elaborate on the core components of this framework: cartilage mechanotransduction, the muscle–bone axis, synovial immunomodulation, and systemic epitranscriptomic regulation.

Schematic of the global RNA–RBP regulatory network in exercise-induced osteoarthritis protection. Mechanical loading stimulates mechanosensors (e.g., Piezo1) in cartilage to remodel RNA–RBP interactions, thereby promoting extracellular matrix (ECM) homeostasis. Simultaneously, the muscle–bone axis utilizes exosomal miRNAs to regulate bone remodeling. In the synovium, exercise-induced factors drive anti-inflammatory macrophage polarization. Systemic epitranscriptomic mechanisms (e.g., m6A methylation) further fine-tune these interactions network-wide. Note: The activation of these protective pathways is dependent on the magnitude and frequency of mechanical loading (dose–response) and may exhibit sex-specific variations, as detailed in the text. Abbreviations: OA, osteoarthritis; RBP, RNA-binding protein; ECM, extracellular matrix.

3.2 Local responses of cartilage tissue

Articular cartilage has a special local response to mechanical stimuli that can help to maintain the joint’s self-balance as well as help in determining the path followed by the course of osteoarthritis (Shao et al., 2024; Yang et al., 2024; Zhang H. et al., 2022; Zhu et al., 2025). Many recent studies show and explain mechanical loading, which causes different expression changes in mechanosensitive circRNAs. We have also seen that the effect of mechanosensitive RNAs is important in regulating cartilage ECM (Chen et al., 2020; Hecht et al., 2019; Wang Z. et al., 2022; Wu et al., 2021; Xiang et al., 2020). Notably, the Piezo1 ion channel, as a mechanosensitive calcium channel, is now considered to be a mediator of this process (Marushack et al., 2025; Qin et al., 2024; Ren et al., 2023). The Piezo1 pathway is markedly activated in a rat model of knee OA caused by excessive mechanical loading, with the corresponding upregulation of Piezo1-associated circRNAs (Deng Z. et al., 2025; Wang S. et al., 2022;