Loss of HDAC5 Accelerates Joint Destruction and Aging During Osteoarthritis

Objectives: Osteoarthritis (OA) lacks effective treatment strategies due to complex pathological mechanisms. In this study, we explored the regulatory role of histone deacetylases 5 (HDAC5) in OA pathogenesis. Methods: . The expression of HDAC5 was detected in the cartilage of humans and mice. Spontaneous OA and experimental OA were performed in wild-type (WT) mice and HDAC5 knockout (KO, HDAC5 −/− ) mice for pathological and immunohistochemical examination. WT and KO mouse chondrocytes were detected by liquid chromatography–mass spectrometry. Metformin (205 mg/kg/day, 4 weeks) was given to identify the modulatory role of HDAC5 in OA pathogenesis. Results: . The expression of HDAC5 was significantly decreased in the cartilage of patients with late-stage OA and of mice subjected to destabilization of the medial meniscus (DMM) surgery. HDAC5 KO accelerated articular cartilage degeneration and chondrosenescence, with increasing expression of matrix metalloproteinases, type X collagen (COL10A1), and p16 ink4a . Moreover, S100 calcium-binding protein A13 (S100A13) was found, and the expression level of S100A13 was upregulated accompanied by decreasing of HDAC5 in OA chondrocytes. In addition, metformin activated HDAC5 and inhibited the S100A13 in OA chondrocytes to abolish OA. Conclusions: . Our findings provide comprehensive evidence of the role and therapeutic potential of HDAC5 in OA.