WTAP improves chondrocyte loss and dysfunctions to ameliorate osteoarthritis through mediating the mA methylation and mRNA stability of IL-33.

Abstract

Osteoarthritis (OA) is a multifactorial degenerative disorder entailing cartilage loss and progressive joint failure. m6A RNA methylation could impact multiple disorders, including OA. In this study, mA methylation regulator WTAP was down-regulated in OA cartilage, accompanied by significantly lower mA methylation levels in OA tissues. In the DMM-induced mice OA model and IL-1β- or TNF-α-stimulated chondrocytes, WTAP and mA methylation levels were decreased, but IL-1β, IL-6, and TNF-α cytokine expressions were elevated. In vivo and in vitro, WTAP overexpression increased mA methylation levels but reduced proinflammatory cytokine contents. Furthermore, WTAP overexpression (OE) increased chondrocyte viability and proliferation, aggrecan and collagen II protein, and decreased cell apoptosis, MMP3, MMP13, and ADAMTS5. WTAP-mediated mA methylation of IL-33 and impaired IL-33 mRNA stability. IL-33 OE caused no changes to WTAP expression; however, IL-33 OE partially attenuated WTAP OE-induced IL-33 downregulation. IL-33 overexpression inhibited chondrocyte viability and proliferation, decreased aggrecan and collagen II but elevated MMP3, MMP13, and ADAMTS5, and increased cell apoptosis and proinflammatory cytokine contents. More importantly, IL-33 eliminated the effects of WTAP OE on chondrocytes. Therefore, WTAP is down-regulated in OA; WTAP improves chondrocyte proliferation and function, thereby ameliorating OA through mediating mA methylation of IL-33 and impairing IL-33 mRNA stability.