The Role And Molecular Mechanism Of CircRNA RERE In Cartilage Degradation Of Osteoarthritis

Objectives N~6-methyladenosine(m6A)is one of the most abundant internal RNA modifications.We investigated the role of m6A-modified circRERE in osteoarthritis(OA)and its mechanism.Materials and methods CircRERE and IRF2 BPL were screened by microarrays.The role of m6A-modification in circRERE was examined by methylated RNA precipitation and morpholino oligo(MOs)treatment.The axis of circRERE/miR-195-5p/IRF2BPL/β-catenin was determined using flow cytometry,western blotting and immunofluorescence in human chondrocytes(HCs)and corroborated using a mouse model of destabilisation of medial meniscus(DMM)with intra-articular(IA)injection of adeno-associated viruses(AAV).Results CircRERE was decreased in OA cartilage and chondrocytes compared with control.CircRERE downregulation was likely attributed to its increased m6 A modification prone to endoribonucleolytic cleavage by YTHDF2-HRSP12-RNase P/MRP in OA chondrocytes.MOs transfection targeting HRSP12 binding motifs in circRERE partially reversed decreased circRERE expression and increased apoptosis in HCs treated with IL-1β for 6 h.CircRERE exerted chondroprotective effects by targeting miR-195-5p/IRF2 BPL,thus regulating the ubiquitination and degradation ofβ-catenin.CircRere(mouse homolog)overexpression by IA-injection of AAV-circRere into mice attenuated the severity of DMM-induced OA,whereas AAV-miR-195a-5p or AAV-sh-Irf2 bpl reduced the protective effects.The detrimental effects of AAV-sh-Irf2 bpl on DMM-induced OA were substantially counteracted by ICG-001,an inhibitor of β-catenin.Conclusions Our study is a proof-of-concept demonstration for targeting m6A-modified circRERE and its target miR-195-5p/IRF2BPL/β-catenin as potential therapeutic strategies for OA treatment.