Vitamin D Alleviates Osteoarthritis Progression by Targeting Cartilage and Subchondral Bone via Myd88-TAK1-ERK Axis Suppression.

Background: Osteoarthritis (OA) causes irreversible joint damage, but current treatments fail to fully address its complex pathology. Emerging evidence suggests subchondral bone metabolic dysfunction may initiate OA. While vitamin D (VitD) is well-established for bone metabolism regulation in osteoporosis, its therapeutic potential in OA remains unclear despite observational studies suggesting protective effects. Our integrated in vivo/in vitro study demonstrates VitD's dual chondroprotective and osteogenic actions in OA.

Methods: Sprague-Dawley rats (n=24) were divided into three groups: sham operation (Sham), OA model (OA), and OA+VitD treatment, with 8 rats in each group. Oral cholecalciferol (2.34 μg/kg/day) was administered for 6 weeks post-Monosodium iodoacetate (MIA) induction. The therapeutic potential of vitamin D was evaluated through a series of in vivo experiments. Human chondrocyte C28 cells were pretreated with TNFα (1ng/mL) to model inflammatory injury, followed by 1,25(OH) D (10 μM) exposure for 72 hours to assess the VitD's effects of chondrogenesis and further investigate its underlying mechanism.

Results: In OA rats, VitD suppressed femoral cartilage degradation (evidenced by 567.76% increased cartilage area, and 39.13% decreased Osteoarthritis Cartilage Histopathology (OACH) score and enhanced subchondral bone mass (61.81% higher BV/TV). At the molecular level, VitD downregulated the expression of cartilage matrix metalloproteinase 13 (MMP13), with a reduction of 74.72% compared to OA group. Additionally, VitD inhibit inflammatory signaling pathways, particularly through the MyD88-TAK1-ERK axis in chondrocytes, and decrease serum IL-6 level. Mechanistic validation of these findings was demonstrated by protein expression reduction of Myd88 (31.22%), phospho-ERK1/2 (66.11%), AP-1 (61.43%) and NFκB (34.36%) compared to OA group. In vitro, VitD also rescued ethanol-induced C28 cell viability loss while significantly upregulating cartilage anabolic markers.

Conclusion: These findings establish VitD as a multimodal OA therapeutic agent targeting both cartilage catabolism and subchondral bone remodeling through Myd88-TAK1-ERK axis.