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Osteoarthritis (OA) is a degenerative disease characterized by joint inflammation and cartilage degeneration due to matrix degradation and chondrocyte apoptosis. Previously, drug therapies have been developed that aim to ease pain and reduce local inflammation. Currently, no effective drug exists that has no significant side effects. Therefore, an unmet medical demand exists for development of tissue-engineering strategies to promote articular cartilage repair and regeneration to treat OA. 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] is an attractive option for articular cartilage repair because of its anti-inflammatory and anti-apoptotic properties. 24R,25(OH)2D3, which is a naturally occurring metabolite of vitamin D3, also has not been shown to cause toxic side effects. Results from the study demonstrate that 24R,25(OH)2D3 can inhibit chondrocyte apoptosis and suppress the production of catabolic factors that result in cartilage degeneration in the in vitro model. Furthermore, although 24R,25(OH)2D3 regulates components of TGF-β1 pathway, the effect of 24R,25(OH)2D3 is not mediated through TGF-β1 signaling. In vivo delivery of 24R,25(OH)2D3 prevented cartilage degeneration and disease progression. In addition, intraarticular injection of 24R,25(OH)2D3 had an effect on cytokines and growth factors production both locally and systemically. Human articular chondrocytes responded to 24R,25(OH)2D3 treatment in both sex and maturation dependent manner. Collectively, results from this study suggest that 24R,25(OH)2D3 ccould be used as a clinical therapy for knee OA.