Mesenchymal stem cell therapy for osteoarthritis: Mechanisms, clinical evidence, and emerging regenerative strategies

Osteoarthritis (OA) is a progressive whole-joint disorder characterized by cartilage degeneration, synovial inflammation, subchondral bone remodeling, and chondrocyte metabolic dysfunction, resulting in chronic pain and disability. Current pharmacologic and surgical treatments offer only symptomatic relief and fail to halt or reverse structural deterioration, underscoring the urgent need for disease-modifying regenerative therapies. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic strategy owing to their multipotent differentiation capacity, immunomodulatory effects, and paracrine actions that support cartilage repair and restore joint homeostasis. This review provides a comprehensive synthesis of the biological mechanisms and clinical applications of MSCs derived from bone marrow, adipose tissue, and umbilical cord sources. Preclinical studies demonstrate that MSCs exert chondroprotective effects by suppressing inflammatory cytokines, regulating macrophage polarization, enhancing extracellular matrix synthesis, and mitigating chondrocyte senescence and mitochondrial dysfunction. Clinical trials consistently report that intra-articular MSC administration improves pain, function, and quality of life in knee OA, with an acceptable safety profile, although therapeutic outcomes vary based on cell source, dose, and patient characteristics. Emerging strategies, including gene-modified MSCs, engineered extracellular vesicles, and biomaterial-assisted delivery systems, substantially enhance MSC retention, targeting, and regenerative potency. Furthermore, combination therapies incorporating MSCs with hyaluronic acid or platelet-rich plasma show synergistic benefits. Collectively, accumulating evidence highlights MSC-based therapy as a promising disease-modifying approach for OA. However, standardized manufacturing, rigorous long-term trials, and optimized patient-specific treatment algorithms are required to accelerate clinical translation.