24R, 25-Dihydroxyvitamin D₃ protects against articular cartilage damage following anterior cruciate ligament transection in male rats

Osteoarthritis (OA) in humans is associated with low circulating 25-hydroxyVitamin D₃ [25 (OH)D₃]. In Vitamin D replete rats, radiolabeled 24R, 25-dihydroxyVitamin D₃ [24R, 25 (OH)₂D₃] accumulates in articular cartilage following injection of [3H]-25(OH)D₃. Previously, we showed that 24R, 25(OH)₂D₃ blocks chondrocyte apoptosis via phospholipase D and p53, suggesting a role for 24R, 25(OH)₂D₃ in maintaining cartilage health. We examined the ability of 24R, 25(OH)₂D₃ to prevent degenerative changes in articular cartilage in an OAlike environment and the potential mechanisms involved. In vitro, rat articular chondrocytes were treated with IL-1β with and without 24R, 25(OH)₂D₃ or 1α, 25(OH)₂D₃. 24R, 25(OH)₂D₃ but not 1α, 25(OH)₂D₃ blocked the effects of IL-1β in a dose-dependent manner, and its effect was partially mediated through the TGF-ß1 signaling pathway. In vivo, unilateral anterior cruciate ligament transections were performed in immunocompetent rats followed by intra-articular injections of 24R, 25(OH)₂D₃ or vehicle (t = 0, 7, 14, 21 days). Tissues were harvested on day 28. Joints treated with vehicle had changes typical of OA whereas joints treated with 24R, 25(OH)₂D₃ had less articular cartilage damage and levels of inflammatory mediators. These results indicate that 24R, 25(OH)₂D₃ protects against OA, and suggest that it may be a therapeutic approach for preventing trauma-induced osteoarthritis.