Chromatin remodeling and epigenetic regulation of mesenchymal stem/stromal cells in osteoarthritis
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.