Cellular senescence in musculoskeletal diseases: biological mechanisms and clinical implications

Cellular senescence is a persistent state of irreversible growth arrest that occurs when cells encounter various stress signals. It is marked by elevated expression of cell cycle inhibitors, dysregulated gene transcription, and secretion of the senescence-associated secretory phenotype (SASP). These senescent features may exert both detrimental and beneficial effects on tissue homeostasis and systemic physiological integrity. In this review, the relevant pathological processes are categorized into three tissue types: skeletal muscle, bone, and cartilaginous tissue. We systematically delineate the mechanisms of cellular senescence underlying seven musculoskeletal diseases, including skeletal muscle injury and regeneration, sarcopenia, osteoporosis, fracture, osteonecrosis of the femoral head (ONFH), osteoarthritis (OA), and intervertebral disc degeneration (IDD), with a particular focus on the heterogeneity of senescent cells across distinct musculoskeletal diseases. On this basis, we further elaborated on relevant mechanisms and senescence-related targets, and analyzed senescence heterogeneity in diverse musculoskeletal tissues, senescence identification and integrated diagnostic approaches. Moreover, we discussed convergent pathways, the dual roles of senescent cells, and the critical evaluation of disease-specific versus common therapeutic vulnerabilities.