Peroxisomal Deficiency Alleviates Temporomandibular Joint Osteoarthritis Cartilage Degradation

This study aims to explore the impact of peroxisome on lipid metabolism and its role in the pathological progression of temporomandibular joint osteoarthritis (TMJOA). The unilateral anterior occlusion (UAC) mouse model, combined with cyclic tensile stress on primary chondrocytes, was used to induce TMJOA pathological progression. Subsequently, Pex2 siRNA and Pex2 flox/flox, Aggrecan-CreERT2 genetic mice were used to generate peroxisomal deficiency. Targeted metabolomics and transcriptomics were employed to identify metabolites affected by peroxisomes and their downstream molecules. Biochemical and histological analyses were conducted to elucidate the molecular mechanisms linking peroxisomes to TMJOA. Peroxisomal deficiency in TMJOA chondrocytes led to a significant reduction in cartilage lesion severity by enhancing extracellular matrix (ECM) anabolism and reducing ECM catabolism. Mechanistically, peroxisomal deficiency significantly reduced palmitic acid (PA) levels, thereby inhibiting the downstream PA-Jnk-c-Jun-S100a4 pathway. As a transcription factor, c-Jun was found to directly activate the transcription of S100a4 by Cut & Run-qPCR analysis, further confirming that the S100a4 gene is a crucial marker for TMJOA. Our research suggests that peroxisomal deficiency markedly reduces TMJOA cartilage degradation through a fatty acid-mediated mechanism. This study provides the first evidence directly linking peroxisomes to TMJOA pathology, suggesting that peroxisomes play a crucial role in TMJOA progression and may serve as a therapeutic target.