Methyltransferase-like 14 mediated FOXP1 m6A modification alleviates osteoporosis by regulating the Wnt/β-catenin pathway

Abstract

The impaired osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) contributes significantly to osteoporosis (OP) pathogenesis. While Forkhead box p1 (FOXP1) is known to regulate stem cell differentiation, its specific role in BMSCs osteogenic differentiation during OP remains unclear. Here, BMSCs were cultured in osteogenic medium for 14 d to induce osteogenic differentiation. We found that FOXP1 was upregulated in BMSCs treated with osteogenic medium, and FOXP1 overexpression promoted BMSC osteogenic differentiation, whereas FOXP1 knockdown inhibited BMSCs osteogenic differentiation. Mechanistically, METTL14 mediated m6A methylation of FOXP1 mRNA, which was recognized by YTHDF1/YTHDF3 to enhance its mRNA stability. Notably, METTL14 overexpression promoted osteogenic differentiation of BMSCs, this effect was abolished by FOXP1 knockdown. The stabilized FOXP1 protein activated the Wnt/β-catenin signaling pathway to drive BMSC osteogenesis. In vivo, administration of FOXP1-overexpressing lentivirus in ovariectomized (OVX) mice significantly attenuated osteoporosis progression. Collectively, our findings reveal that METTL14-dependent m6A modification and YTHDF1/YTHDF3-mediated stabilization of FOXP1 alleviate osteoporosis in OVX mice through Wnt/β-catenin activation, positioning FOXP1 as a promising therapeutic target for postmenopausal osteoporosis.