YTHDF2-driven degradation of BARX2 mRNA accelerates osteoarthritis progression by enhancing the TOP2A/WNT/β-Catenin...

Emerging evidence highlights the critical role of transcription factors (TFs) in diverse diseases, including osteoarthritis (OA). However, the identification of key TFs in OA pathogenesis needs further understanding. BarH-like homeobox 2 (BARX2), significantly downregulated in osteoarthritis (OA) cartilage and IL-1β-stimulated chondrocytes, plays a protective role in OA pathogenesis. Mechanistically, methyltransferase-like 3 (METTL3) / methyltransferase-like 14 (METTL14) complex-mediated N6-methyladenosine (m6A) modification was found to enhance BARX2 mRNA degradation via the YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) - dependent manner, resulting in decreased BARX2 expression in osteoarthritic human chondrocytes. BARX2 was shown to mitigate interleukin-1beta (IL-1β) - induced damage in osteoarthritic human chondrocytes by suppressing Wnt / β-catenin signaling pathway. Conversely, BARX2 knockdown exacerbated this damage. Additionally, we discovered that BARX2 inhibited the activation of Wnt / β-catenin pathway and reduced IL-1β-induced osteoarthritic chondrocyte damage by binding to the topoisomerase II alpha (TOP2A) promoter to suppress TOP2A transcriptional expression. Lastly, our data demonstrated that BARX2 ameliorate OA progression by inhibiting TOP2A-mediated Wnt / β-catenin pathway activation in DMM-induced male OA mice. In conclusion, YTHDF2-mediated decay of m6A-modified BARX2 mRNA by METTL3/14 reduces BARX2 levels, contributing to OA progression via upregulation of TOP2A and consequent activation of the Wnt/β-catenin pathway.