Extracellular vesicles from glucocorticoids‐preconditioned synovial mesenchymal stem cells exert antiarthritic effects by downregulating the mRNA m6A modification of NLRP3 in macrophages through miR‐212‐5p

Abstract

Osteoarthritis (OA) is a prevalent chronic degenerative joint disease with no known treatment for reversing its progression. However, recent studies have shown promising results for nano‐sized extracellular vesicles derived from preconditioned synovial mesenchymal stem cells (SMSCs) in treating various diseases, including OA. Glucocorticoids (GCs) possess potent anti‐inflammatory properties, but their long‐term use is limited due to potential adverse reactions. Building on previous research, this study aimed to investigate the therapeutic potential of extracellular vesicles secreted from GCs‐pretreated SMSCs (GCs‐EVs) in exerting antiarthritic effects. The results demonstrated that GCs‐EVs effectively inhibited cartilage degeneration and osteophyte formation in the OA mouse model by suppressing the release of inflammatory cytokines from synovial macrophages. This effect was attributed to the high expression of miR‐212‐5p in GCs‐EVs, which specifically inhibited the expression of methyltransferase‐like 3 (Mettl3). Consequently, the mRNA N6‐methyladenosine (m6A) level of nod‐like receptor pyrin domain 3 inflammasome (NLRP3) in macrophages was reduced, leading to decreased NLRP3 inflammasome activity and increased antiarthritic effects. Furthermore, in the co‐culture system, GCs‐EVs enhanced chondrocyte proliferation and migration while inhibiting chondrocyte apoptosis by suppressing the secretion of inflammatory factors by macrophages.