HDAC6 exacerbates osteoarthritis by promoting macrophage inflammation-mediated chondrocyte degeneration.

Abstract

Osteoarthritis (OA) is a degenerative joint disorder characterized by cartilage degradation and synovial inflammation, with its pathogenesis involving intricate interactions between cellular metabolic processes and inflammatory pathways. In this study, we established OA models in both wild-type and histone deacetylase 6 (HDAC6) knockout mice via anterior cruciate ligament transection (ACLT) to investigate the role of HDAC6 in OA progression. Histological and immunohistochemical analyses revealed that the absence of HDAC6 significantly mitigated ACLT-induced cartilage damage and synovitis in mice, while also restoring imbalances in cartilage metabolic markers. In vitro experiments demonstrated that, upon stimulation with inflammatory factors IL-1β or TNF-α, neither HDAC6 overexpression nor knockdown significantly altered the metabolic processes of chondrocytes, suggesting that HDAC6 may not directly regulate chondrocyte metabolism in an inflammatory context. However, conditioned medium from macrophages overexpressing HDAC6 promoted catabolic processes in chondrocytes and inhibited anabolic processes, whereas the knockdown of HDAC6 reversed this effect. These findings imply that HDAC6 contributes to the progression of OA by amplifying macrophage-mediated synovial inflammation, thereby indirectly disrupting the metabolic homeostasis of chondrocytes. In conclusion, these results suggest that targeting HDAC6 may provide a novel strategy for alleviating OA pathology by modulating macrophage-chondrocyte interactions.