Peroxisome Functional Inhibition Alleviates TMJOA Cartilage Degradation

Temporomandibular joint osteoarthritis (TMJOA) is a progressive and debilitating degenerative joint disorder characterized by cartilage degradation. Its pathogenesis remains poorly understood, and current treatment strategies are insufficient to restore normal joint structure. Lipid metabolism disorders in condylar chondrocytes have been identified as key contributors to TMJOA development, with peroxisomes playing an essential regulatory role in this metabolic process. Although previous studies have suggested a role for peroxisomes in chondrocyte biology, their specific involvement in TMJOA pathogenesis remains unclear. This study is the first to demonstrate the involvement of peroxisomes in TMJOA and to elucidate the associated molecular mechanisms. A TMJOA mouse model was established via unilateral anterior crossbite surgery, revealing abnormal peroxisome quantity and function. In vitro experiments demonstrated that inhibiting peroxisome function alleviated mechanical stress-induced OA-like damage to chondrocytes. In <i>Acan</i>-CreER^T2 <i>Pex2</i>^f/f conditional knockout (KO) mice, <i>Pex2</i> KO inhibited peroxisome function and significantly attenuated TMJOA pathology. Mechanistically, peroxisome functional inhibition led to decreased levels of palmitic acid (PA), whereas exogenous PA exposure induced an OA-like phenotype in chondrocytes. Further investigation revealed that PA activated the WNT/PCP pathway by activating the JNK/c-JUN signaling axis. Multiomics analysis revealed <i>S100a4</i> as a key downstream effector gene, and further CUT&RUN quantitative polymerase chain reaction and dual-luciferase reporter assays confirmed that c-JUN directly bound to the <i>S100a4</i> promoter region (-101 to -94 bp) to regulate its transcription. Knockdown of <i>S100a4</i> expression significantly reduced PA-induced <i>Mmp13</i> expression in chondrocytes. In vivo experiments confirmed that intra-articular injection of PA upregulated <i>S100a4</i> levels and promoted TMJOA development. In conclusion, this study is the first to elucidate the critical role of the peroxisome/PA/JNK/c-JUN/<i>S100a4</i> axis in cartilage degradation in TMJOA, providing a novel and promising therapeutic target for TMJOA.