Epigenetic PPARγ preservation attenuates temporomandibular joint osteoarthritis

Objective: Previous studies have demonstrated that PPAR gamma deficiency is associated with osteoarthritis in the knee joint. However, whether epigenetic PPAR gamma dysregulation has any effect on temporomandibular joint osteoar-thritis (TMJOA) is unknown. This study aims to determine the role and mechanism of epigenetic PPAR gamma dys-regulation in TMJOA.Methods: Partial TMJ discectomy was performed to induce TMJOA in rat. Primary condylar chondrocytes were isolated, and TNF-alpha-induced inflammatory condition was created in vitro. The expressions of PPAR gamma and DNA methyltransferase were investigated in vivo and in vitro. The association of PPAR gamma and DNA methylation was further studied by treating chondrocytes with DNA demethylation agent 5-Aza-2 '-deoxycytidine (5Aza) and transfecting with siRNA of DNA methyltransferase (DNMT)1 and DNMT3a, and the methylation level of PPAR gamma promoter was evaluated by Bisulfite-sequencing PCR. The chondroprotective effects of 5Aza were explored in vitro and in vivo.Results: PPAR gamma suppression and upregulated DNMT1/DNMT3a expression exist in TMJOA cartilage in vivo and primary condylar chondrocytes under TNF-alpha-induced inflammatory conditions in vitro. DNMT1 and DNMT3a elevation contributes to PPAR gamma-promoter hypermethylation in TMJ chondrocytes under TNF-alpha-induced inflam-mation conditions. DNA demethylation intervention by 5Aza protects chondrocytes from inflammation response in vitro. Mechanistically, 5Aza reversed the hypermethylation of the PPAR gamma promoter and subsequently resulted in PPAR gamma restoration and decreased expression of cartilage-catabolic factors in chondrocytes. Rat TMJOA model revealed that 5Aza, by reversing PPAR gamma suppression, effectively attenuated cartilage degeneration and stabilized cartilage homeostasis by balancing anabolic factor and catabolic factor expression.Conclusion: Epigenetic PPAR gamma suppression may play a causal role in TMJOA pathogenesis, which can be alle-viated by DNA demethylation with 5Aza treatment. This study provides new insights into the pathogenic mechanism and therapeutic strategy of TMJOA.

Automated summary

This study reveals the significant role of epigenetic PPAR gamma dysregulation in the pathogenesis of TMJOA. The suppression of PPAR gamma can be alleviated by DNA demethylation intervention, leading to cartilage restoration and stabilizing cartilage homeostasis.