The Otto Aufranc Award: DNMT3A-PPARγ Signaling Is a Key Epigenetic Mechanism of Hip Osteoarthritis Disease: A Potential Therapeutic Target

Background: Femoroacetabular impingement is the leading cause of hip osteoarthritis (OA) and has been linked to 50% of total hip arthroplasty (THA) cases. Still, the mechanism by which the joint progresses to OA remains unknown. Previous studies indicate that peroxisome proliferator-activated receptor gamma (PPARγ) suppression occurred during hip OA progression. We have observed the hypermethylation of the CpG PPARγ promoter area through DNA methyltransferase 3A (DNMT3A), resulting in cartilage catabolism and hip OA. However, its precise mechanism remains unclear. We hypothesized that DNMT3A gain-of-function (GOF) leads to chondrocyte catabolism through PPARγ suppression, and DNMT3A loss-of-function (LOF) rescues the catabolism in OA chondrocytes. Methods: Healthy chondrocytes were isolated from osteochondral allografts, and OA chondrocytes from patients undergoing THA secondary to femoroacetabular impingement disease. Chondrocytes were treated to evaluate the GOF and LOF effects of DNMT3A using lentiviral particles. Interleukin 1 beta (IL1β) was used to mimic the OA phenotype in healthy chondrocytes. Groups included a scramble control, DNMT3A GOF, IL1β+scramble control, IL1β+DNMT3A GOF, and IL1β+DNMT3A LOF for healthy chondrocytes, and scramble control, DNMT3A GOF, and DNMT3A LOF for OA chondrocytes. The DNMT3A, PPARγ, Col2, and MMP13 expression levels were analyzed, with significance set at P < 0.05. Results: The IL1β treatment and DNMT3A GOF in healthy chondrocytes significantly increased DNMT3A and MMP13 while decreasing PPARγ and Col2 expression. The DNMT3A LOF in IL1β-treated chondrocytes increased PPARγ and Col2 and decreased MMP13 expression. In OA chondrocytes, DNMT3A GOF increased MMP13 expression while suppressing PPARγ and Col2, whereas DNMT3A LOF resulted in opposite effects, suggesting DNMT3A LOF treatment can alleviate catabolic changes. Conclusions: The DNMT3A LOF treatment partly reversed chondrocyte degeneration and catabolism, positioning the modulation of DNMT3A as a potential therapeutic intervention in hip OA progression.