PPARγ preservation via promoter demethylation alleviates osteoarthritis in mice

Objectives Osteoarthritis (OA) is the most common degenerative joint disease in aged population and its development is significantly influenced by aberrant epigenetic modifications of numerous OA susceptible genes; however, the precise mechanisms that DNA methylation alterations affect OA pathogenesis remain undefined. This study investigates the critical role of epigenetic PPAR gamma (peroxisome proliferator-activated receptor-gamma) suppression in OA development. Methods Articular cartilage expressions of PPAR gamma and bioactive DNA methyltransferases (DNMTs) from OA patients and mice incurred by DMM (destabilisation of medial meniscus) were examined. DNA methylation status of both human and mouse PPAR gamma promoters were assessed by methylated specific PCR and/or bisulfite-sequencing PCR. OA protections by a pharmacological DNA demethylating agent 5Aza (5-Aza-2'-deoxycytidine) were compared between wild type and PPAR gamma knockout mice. Results Articular cartilages from both OA patients and DMM mice display substantial PPAR gamma suppressions likely due to aberrant elevations of DNMT1 and DNMT3a and consequential PPAR gamma promoter hypermethylation. 5Aza known to inhibit both DNMT1 and DNMT3a reversed the PPAR gamma promoter hypermethylation, recovered the PPAR gamma loss and effectively attenuated the cartilage damage in OA mice. 5Aza also inhibited the OA-associated excessive inflammatory cytokines and deficit anti-oxidant enzymes, which were blocked by a specific PPAR gamma inhibitor in cultured chondrocytes. Further, 5Aza-confered protections against the cartilage damage and the associated abnormalities of OA-susceptible factors were significantly abrogated in PPAR gamma knockout mice. Conclusion Epigenetic PPAR gamma suppression plays a key role in OA development and PPAR gamma preservation via promoter demethylation possesses promising therapeutic potentials in clinical treatment of OA and the related joint diseases.