PPARγ preservation via promoter demethylation alleviates osteoarthritis in mice

Abstract

ObjectivesOsteoarthritis (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 PPARγ (peroxisome proliferator–activated receptor-gamma) suppression in OA development.MethodsArticular cartilage expressions of PPARγ 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 PPARγ 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 PPARγ knockout mice.ResultsArticular cartilages from both OA patients and DMM mice display substantial PPARγ suppressions likely due to aberrant elevations of DNMT1 and DNMT3a and consequential PPARγ promoter hypermethylation. 5Aza known to inhibit both DNMT1 and DNMT3a reversed the PPARγ promoter hypermethylation, recovered the PPARγ 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 PPARγ inhibitor in cultured chondrocytes. Further, 5Aza-confered protections against the cartilage damage and the associated abnormalities of OA-susceptible factors were significantly abrogated in PPARγ knockout mice.ConclusionEpigenetic PPARγ suppression plays a key role in OA development and PPARγ preservation via promoter demethylation possesses promising therapeutic potentials in clinical treatment of OA and the related joint diseases.

Nanosecond pulsed electric fields enhance mesenchymal stem cells differentiation via DNMT1-regulated OCT4/NANOG gene expression

“…Despite all this, the parameters applying in iPSCs could be different from those in MSCs, because we found that only one set paraments of nsPEFs, 100 ns at 10 kV/cm, can regulate OCT4/NANOG in hESCs, which suggested that different cell types may need more detailed parameter segmentations. Another potential future application scenario of nsPEFs is in disease treatment, since the downregulation of DNMT1 has been reported to be able to promote the relief of the osteoarthritic symptoms in chondrocyte [49]. We have analyzed the proteomics of MSCs and found that among 3808 proteins, 59 were increased (fold change > 1.33), and 44 were downregulated (fold change < 0.75) at 2 h after nsPEF treatment, among which 6 proteins were related to epigenetic regulation (data not shown).…”

Exhausting circ_0136474 and Restoring miR-766-3p Attenuate Chondrocyte Oxidative Injury in IL-1β-Induced Osteoarthritis Progression Through Regulating DNMT3A

“…In addition, Wu et al (Chen et al, 2017) claimed that the promoter of miR-766-3p was highly methylated in renal cell carcinoma tissues, suggesting that DNA methylation could, in turn, control miR-766-3p expression as well. Plus, PPARγ played a key role in OA development, and its promoter hypermethylation was attributed to DNMT3A and DNMT1 (Zhu et al, 2019). These finding suggested a possible regulatory back loop of miR-766-3p/DNMT3A in OA chondrocytes; however, this hypothesis was left to be further deciphered, as well as the discovery of DNMT3A downstream targets.…”

Ultrasound-targeted Simvastatin-loaded Microbubble Destruction Promotes OA Cartilage Repair by Modulating Cholesterol Efflux Pathway Mediated by PPARγ in Rabbits.

“…Studies have shown that PPARγ affects chondrocytes metabolism and lipid metabolism and participates in the occurrence and development of OA. Direct activation of PPARγ can promote cholesterol e ux and reduce lipid deposition in chondrocytes [33] . In our study, we found that the cholesterol e ux rate decreased signi cantly after inhibiting PPARγ, and the cholesterol e ux rate increased after the PPARγ combined with UTMDsv intervention.…”