Fibrotic remodeling and stromal reprogramming in osteoarthritis: mechanisms, mechanobiology, and emerging therapeutic perspectives

Osteoarthritis (OA) has traditionally been regarded as a degenerative joint disorder characterized primarily by cartilage erosion. However, growing evidence suggests that OA is a disorder of maladaptive whole-joint remodeling in which fibrotic remodeling represents an important yet underappreciated contributor to disease progression. Fibrotic remodeling is best documented in the synovium and joint capsule, with related stromal and extracellular matrix (ECM) changes also occurring in the infrapatellar fat pad and other joint compartments. Recent studies suggest that OA-associated fibrotic remodeling extends beyond passive scar formation and involves persistent stromal reprogramming, chronic inflammatory signaling, and mechanobiological adaptation. In this review, stromal reprogramming is used as a conceptual framework describing persistent alterations in stromal cell state that extend beyond transient fibroblast activation or fibroblast-to-myofibroblast transition (FMT). These alterations may involve sustained transcriptional programs, altered mechanosensitivity, metabolic or epigenetic adaptation, and incomplete restoration of tissue homeostasis. However, direct evidence demonstrating stable long-term stromal reprogramming in human OA remains limited. Advances in single-cell omics, spatial transcriptomics, and systems biology approaches have revealed substantial heterogeneity among stromal and immune cell populations, providing new insights into fibrosis-associated cellular states and potential opportunities for biomarker-guided patient stratification. Nevertheless, whether these states represent stable biological entities, transitional disease stages, or secondary responses to advanced OA remains unresolved. This review focuses on the unresolved transition from adaptive tissue repair to persistent fibrotic remodeling and proposes a conceptual framework linking stromal reprogramming, inflammatory signaling, ECM remodeling, and mechanobiological feedback during OA progression. Throughout, we distinguish direct evidence from human OA and experimental OA models from mechanistic insights derived from rheumatoid arthritis and other fibrotic diseases. We further discuss emerging precision medicine strategies and future opportunities for biomarker-guided and mechanobiology-informed antifibrotic interventions. Although this Review adopts a whole-joint perspective, current mechanistic evidence remains predominantly synovium-centered, highlighting the need for further investigation of fibrotic remodeling across additional joint compartments.