METTL3-IGF1-AKT signaling promotes endochondral ossification during bone fracture healing (PRJCA049196)
Bone fractures represent a significant and growing global health issue, with non-union fractures severely compromising patients' quality of life. Fracture healing occurs primarily through endochondral ossification; however, the regulatory mechanisms underlying this process remain incompletely understood. Thus, elucidating the molecular basis of endochondral bone formation is essential for advancing fracture treatment.m6A is the most abundant chemical modification in mammalian mRNA and plays a crucial role in cell fate determination and differentiation. Yet, the function of the m6A RNA methylome in bone fracture healing has not been defined.  Genetic deletion of METTL3 in preosteoblasts led to increased apoptosis of hypertrophic chondrocytes and delayed fracture healing. Mechanistically, METTL3 promotes the expression of IGF1 in an m6A-dependent manner, which facilitated osteogenesis of hypertrophic chondrocytes and suppresses apoptosis via activation of the AKT signaling pathway. Restoration of IGF1 expression rescued the impaired osteogenesis and delayed healing observed in METTL3-deficient mice. Together, our findings highlight the critical role of the METTL3-IGF1-AKT axis in endochondral ossification and suggest a potential therapeutic strategy for treating delayed fracture healing