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

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.