Osteoarthritis (OA) is a common chronic degenerative joint disease characterized by progressive cartilage destruction, synovial inflammation, subchondral bone remodeling, and functional decline. Current treatments remain largely symptomatic and are unable to effectively halt or reverse disease progression. Increasing evidence indicates that epigenetic regulation provides a critical link between genetic susceptibility, mechanical loading, inflammation, aging, metabolic abnormalities, and pathological gene expression in OA. This review summarizes recent advances in OA epigenetics, with a particular focus on studies published over the past 2 years. We discuss classical mechanisms, including DNA methylation, histone modifications, and non-coding RNA-mediated regulation, and further highlight emerging epigenomic layers such as chromatin accessibility, enhancer and super-enhancer remodeling, three-dimensional genome organization, tissue-specific regulation, and the integration of genetics with single-cell and spatial multi-omics. These mechanisms contribute to inflammatory activation, chondrocyte metabolic imbalance, extracellular matrix degradation, programmed cell death, cellular senescence, oxidative stress, and abnormal inter-tissue crosstalk. Epigenetic biomarkers and epigenetic-based interventions, including extracellular vesicle-mediated delivery, engineered RNA therapeutics, and small-molecule epigenetic drugs, may offer new opportunities for early diagnosis, disease stratification, and precision therapy. However, current studies are limited by model heterogeneity, sample variability, insufficient causal validation, limited reproducibility, and translational challenges related to delivery and safety. Overall, epigenetic regulation provides a systematic framework for understanding OA heterogeneity and progression and may promote the development of disease-modifying therapeutic strategies.
Osteoarthritis (OA) creates a persistently hostile joint microenvironment in which inflammatory, mechanical, metabolic, oxidative, and senescence-related cues alter the behavior of mesenchymal stem/stromal cells (MSCs). These changes are not limited to short-term signaling responses, but they should not be interpreted as fixed or irreversible cellular states. Depending on the duration and intensity of environmental exposure, some MSC responses may be transient and reversible, whereas others may be reinforced through epigenetic and chromatin-state regulation, potentially contributing to impaired chondrogenic differentiation, accelerated cellular senescence, and altered paracrine activity, including extracellular vesicles (EVs)-related functions. In this review, we discuss how DNA methylation, histone modifications, long non-coding RNA (lncRNA)-mediated complex recruitment and RNA modifications, chromatin accessibility, and adenosine triphosphate (ATP)-dependent chromatin remodeling connect OA-related stress with OA-associated functional alterations of MSCs. Particular attention is given to the position of chromatin remodeling within the broader epigenetic network. Rather than acting as a separate mechanism, chromatin remodeling provides a structural layer through which regulatory marks, enhancer activity, nucleosome positioning, and transcription-factor access are translated into transcriptional outcomes. We also distinguish different levels of evidence. Data linking epigenetic regulation to MSC chondrogenesis are relatively strong, whereas direct evidence that specific chromatin events determine cargo loading into EVs remains limited. Chromatin regulators such as histone deacetylases (HDACs), BRG1/SMARCA4, and SMARCA5 may serve as mechanistic entry points, but findings from chondrocytes or general MSC models should not be directly extrapolated to OA-derived MSCs without further validation. Finally, we discuss rejuvenation of MSCs, epigenetic preconditioning, microenvironmental engineering, and optimization of EVs as potential strategies for OA regenerative therapy, while emphasizing product heterogeneity, potency testing, patient stratification, and long-term safety as major barriers to translation.
Mo Wu, Cenzhuo Sheng, Hanhao Zhang et al.· Frontiers in Genetics· 0 citations
Osteoarthritis (OA) is a chronic degenerative joint disease closely associated with aging and metabolic dysfunction, characterized by cartilage degeneration, synovial inflammation, aberrant subchondral bone remodeling, pain and progressive functional impairment. Beyond mechanical loading, accumulating evidence indicates that OA is increasingly recognized as a whole-joint disorder shaped by the interplay between local tissue damage and systemic endocrine-metabolic imbalance. Endocrine factors, including sex hormones, thyroid hormone, melatonin, parathyroid hormone and vitamin D, together with metabolic disturbances, such as obesity, insulin resistance, dysregulated glucose and lipid metabolism and gut microbiota imbalances, can cooperatively remodel the joint microenvironment. Mechanistically, these alterations converge on immuno-inflammatory amplification, mitochondrial dysfunction, oxidative stress, cellular senescence, metabolic reprogramming and regulated cell death, thereby promoting extracellular matrix degradation, persistent synovitis and uncoupled bone-cartilage remodeling. The present review systematically summarizes the molecular basis of endocrine-metabolic crosstalk in OA and discusses emerging therapeutic opportunities targeting hormonal signaling, metabolic pathways, circadian regulation, nutritional support and lifestyle interventions. Nevertheless, the reciprocal interactions among endocrine signals, systemic metabolic abnormalities and local joint pathology remain incompletely understood, and their translation into mechanism-based clinical stratification remains at an early stage. Thus, targeting endocrine-metabolic crosstalk may support mechanism-based phenotyping and subtype-informed precision therapy for OA, provided that candidate biomarkers and interventions are validated in prospective clinical studies.
Ruhui Yang, Haimin Zeng, Qi Xiao et al.· International Journal of Mol...· 1 citation
Aging of the skeleton is a hallmark of organismal decline and underlies prevalent age-related disorders such as osteoporosis and osteoarthritis. Bone marrow-derived mesenchymal stem cells (BMSCs), the primary source of osteoblasts, undergo profound functional deterioration during senescence, leading to an imbalance between bone formation and resorption. This review systematically summarizes the key features of BMSC senescence, including impaired proliferation and differentiation, epigenetic dysregulation, and the acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP). We highlight recent advances in understanding how epigenetic mechanisms (DNA methylation, histone modifications, RNA methylation, and non-coding RNAs) orchestrate BMSC aging. In addition, we discuss the intricate crosstalk between senescent BMSCs and the bone microenvironment, emphasizing their contribution to age-related bone diseases. Finally, we propose future research directions, including the integration of multi‑omics, single-cell technologies, and targeted epigenetic interventions, as well as emerging therapeutic strategies such as senolytics, metabolic modulators, and extracellular vesicle-based approaches. A deeper understanding of BMSC aging will facilitate the development of novel treatments to preserve bone health and combat aging-related skeletal disorders.
Zimo Zhou, Heran Wang, Zhuoru Jin et al.· Ageing Research Reviews· 1 citation
It is highlighted that future OA treatment may gradually shift from symptom-oriented management toward disease-modifying therapy based on the identification of immune endotypes, and further studies are required to validate the underlying molecular mechanisms, evaluate safety, and conduct clinical trials, thereby facilitating the clinical translation of immune reprogramming strategies for OA.
Tong Wang, Wei Jiang, Xingxu Chen et al.· Frontiers in Immunology· 0 citations
Background:
Osteoarthritis (OA) is a multifaceted age-related joint disorder resulting from the interplay of metabolic, inflammatory, and senescent pathways. This review combines the most recent research on the interconnected signaling networks in OA and aging.
Methods:
A systematic search of major databases was performed from 2010 to 2025 in accordance with PRISMA guidelines. Included were studies that examined specific molecular targets and signaling pathways in OA or joint degeneration associated with aging. The Newcastle-Ottawa Scale was used to rate quality.
Results:
The study shows that OA is a multi-pathway aging disorder that leads to cartilage destruction by combining the senescence-associated secretory phenotype (SASP), epigenetic dysregulation, metabolic dysfunction, and impaired mechanotransduction. The RUNX2/SPP1 axis encourages hypertrophic change, while METTL3-mediated m6A changes stop autophagy. Sirtuins (SIRT1/SIRT6) are essential for regulating metabolism, and Klotho contributes to both Wnt suppression and oxidative stress resistance. Inflammaging is linked to senescence through STAT3, a key mediator of the process.
Conclusion:
OA is a systemic aging disorder that necessitates multi-target strategies. Senolytic agents, METTL3 inhibitors, SIRT activators, Klotho-based biologics, and combinations targeting STAT3-MAPK-driven inflammaging are among the most important therapeutic directions. For future translation, we need validated biomarkers to group patients and long-term safety data.
S. Jami, Ahmed Abu Ryash, Fayez Abidah et al.· Voice of Doctors Journal· 0 citations
