Cellular Senescence in Osteoarthritis: Mechanisms, Pathological Roles, and Therapeutic Opportunities

Abstract

Osteoarthritis (OA) is a prevalent whole‐joint disorder characterized by progressive alterations in articular cartilage, synovium, subchondral bone, and surrounding tissues. Increasing evidence implicates cellular senescence as a potential contributor to OA‐associated tissue dysfunction, although the extent and direction of causality remain incompletely defined. Senescent cells have been identified in several joint compartments and may exhibit a senescence‐associated secretory phenotype (SASP) that influences inflammatory signaling, extracellular matrix turnover, and tissue homeostasis. This review summarizes the cellular and molecular mechanisms associated with senescence in OA, including DNA damage, oxidative stress, mitochondrial dysfunction, mechanical stress, epigenetic alterations, and changes in mesenchymal stem/stromal cell function. Particular attention is given to the heterogeneity of senescence across chondrocytes, synovial fibroblasts and macrophages, subchondral bone cells, and mesenchymal stem/stromal cells. The limitations of commonly used senescence markers are also considered, emphasizing the need for multimarker and functional assessment. Senolytic and senomorphic strategies are reviewed according to their experimental and clinical evidence. Although several interventions have shown beneficial effects in cellular and animal models, clinical evidence in OA remains limited. The contrasting experience with UBX0101 further illustrates the challenges of translating senescence‐targeted approaches from preclinical models to patients. Key issues include target specificity, biomarker validation, incomplete senescent‐cell clearance, off‐target effects, tissue‐specific delivery, and long‐term safety. Overall, senescence‐targeted therapies remain investigational and require further validation before their disease‐modifying potential in OA can be established in human OA with confidence.