p16INK4a downregulation alleviates temporomandibular joint osteoarthritis combined with type 2 diabetes by driving M2 polarization.

Temporomandibular joint osteoarthritis (TMJOA), sometimes combined with type 2 diabetes (T2DM-TMJOA), has a restricting effect on quality of life and currently has few efficacious treatment options. As such, this project sought to determine the role of p16INK4a (p16) in T2DM-TMJOA development. In vivo, p16 knockout (P16KO) mice experienced less condylar bone loss and altered macrophage polarities from the inflammatory M1 to anti-inflammatory M2. In vitro, p16 knockdown (P16KD) or MS37452 treatment of THP-1 cells under high glucose and high palmitoleic acid conditions inhibited inflammatory angiogenesis and lymphangiogenesis, and supported osteogenic differentiation, respectively. Mechanistically, P16KD modelling restored mitochondrial functionality, limited intracellular iron accumulation, and polarized M2 macrophages through glutathione (GSH). Collectively, these data identify p16 as a critical regulator of T2DM-TMJOA and provide evidence for a future treatment strategy by therapeutic inhibition of p16.