Long non-coding RNA MEG3 inhibits chondrogenic differentiation of synovium-derived mesenchymal stem cells by epigenetically inhibiting TRIB2 via methyltransferase EZH2

Abstract

Osteoarthritis (OA) is a highly prevalent skeletal disease. Mesenchymal stem cell-derived cartilage tissue engineering is a clinical method used for OA treatment. Investigations on the molecular regulatory mechanisms of the chondrogenic differentiation of synovium-derived mesenchymal stem cells(SMSCs) will help promote its clinical applications. In this study, bioinformatics analysis from three different databases indicated that the long non-coding RNA (lncRNA) MEG3 may regulate the chondrogenic differentiation of SMSCs by targeting TRIB2. We then performed assays and found that both knockdown of MEG3 or overexpression of TRIB2 can stimulate the chondrogenic differentiation of SMSCs and increase Col2A1 and aggrecan expression. Knockdown of MEG3 can induce the expression of TRIB2; conversely, overexpression of MEG3 can inhibit the expression of TRIB2. Futhermore, knockdown of the TRIB2 can rescue the MEG3 silencing-mediated promotion of chondrogenic differentiation. Moreover, RNA immunoprecipitation(RIP) and RNA pull-down assays demonstrated that MEG3 can interact with EZH2, thus recruiting it to induce H3K27me3, which promotes the methylation of TRIB2 by binding with the promoter of TRIB2 in SMSCs. Additionally, EZH2 silencing significantly rescued the MEG3 overexpression-mediated inhibition of TRIB2 expression and chondrogenic differentiation of SMSCs. Taken together, these data indicated that MEG3 regulates chondrogenic differentiation by inhibiting TRIB2 expression through EZH2-mediated H3K27me3.