TGFBI Maintains Fibrocartilage Homeostasis by Restraining O-GlcNAcylation to Inactivate and Destabilize ADAMTS16 in Temporomandibular Joint Osteoarthritis.

The mandibular condyle is covered by fibrocartilage, and its degeneration, termed temporomandibular joint osteoarthritis (TMJOA), currently lacks effective disease-modifying therapies. In this study, we uncover a previously unrecognized mechanism by which the extracellular matrix protein TGFBI (TGF-β-induced) sustains condylar fibrocartilage homeostasis by restraining protein O-GlcNAcylation. We demonstrate that TGFBI is predominantly expressed in the condylar perichondrium and is markedly downregulated in both TMJOA patients and corresponding mouse models. Genetic ablation of Tgfbi delays postnatal skeletal development, promotes chondrocyte hypertrophy, and accelerates fibrocartilage degeneration. Mechanistically, TGFBI functions as a negative regulator of O-GlcNAcylation in condylar perichondrial cells (cPCs), thereby suppressing both the transcriptional activation and protein stability of the matrix protease ADAMTS16. Notably, ex vivo studies identify Ser1170 of ADAMTS16 as a critical O-GlcNAcylation site that directly governs its protein turnover. By inhibiting O-GlcNAcylation at this residue, TGFBI prevents condylar chondrocyte hypertrophy, senescence, and extracellular matrix degradation. Collectively, our findings establish the TGFBI-O-GlcNAcylation-ADAMTS16 axis as a vital driver of condylar fibrocartilage degeneration and highlight a promising metabolic target for TMJOA therapy.