Secretome Derived from Umbilical Cord Mesenchymal Stem Cells as a Therapeutic Approach for Osteoarthritis: Insights from In Vitro, In Vivo, and Clinical Evidence.

Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by articular cartilage deterioration, synovial inflammation, and progressive loss of joint function. Current treatments predominantly address symptoms without modifying structural disease progression, highlighting the need for disease-modifying strategies. Mesenchymal stem cells (MSCs), particularly umbilical cord-derived MSCs (UC-MSCs), exert therapeutic effects primarily through paracrine mechanisms rather than direct engraftment. The UC-MSCs secretome, comprising soluble bioactive factors and extracellular vesicles, modulates pro-inflammatory signaling, inhibits chondrocyte apoptosis, and promotes cartilage matrix biosynthesis. In vitro studies demonstrate restoration of anabolic chondrocyte phenotype, suppression of catabolic enzymes (MMP-13, ADAMTS-5), and attenuation of NF-κB and MAPK pathway activation. Preclinical models show preservation of cartilage architecture, reduced synovial inflammation, and improved joint function following intra-articular administration. Early clinical investigations report reductions in pain scores and functional improvements with favorable short-term safety profiles, though evidence remains largely derived from MSCs-based rather than secretome-specific interventions. Current findings support the biological plausibility and translational potential of UC-MSCs secretome therapy; however, clinical evidence remains limited and heterogeneous. Adequately powered randomized controlled trials with standardized protocols and extended follow-up are required to establish long-term efficacy and safety.