Melatonin antagonizes bone loss induced by mechanical unloading via IGF2BP1-dependent m⁶A regulation

Disuse bone loss is prone to occur in individuals who lack mechanical stimulation due to prolonged spaceflight or extended bed rest, rendering them susceptible to fractures and placing an enormous burden on social care; nevertheless, the underlying molecular mechanisms of bone loss caused by mechanical unloading have not been fully elucidated. Numerous studies have focused on the epigenetic regulation of disuse bone loss; yet limited research has been conducted on the impact of RNA modification bone formation in response to mechanical unloading conditions. In this study, we discovered that m⁶A reader IGF2BP1 was downregulated in both osteoblasts treated with 2D clinostat and bone tissue in HLU mice. Supplementing IGF2BP1 could promote osteoblast proliferation and partially alleviate the adverse effects of mechanical unloading on bone formation. Mechanistically, IGF2BP1 inhibited the degradation of Lef1 mRNA by directly binding to its mRNA and recognizing the m⁶A modification. Furthermore, LEF1 promoted osteoblast proliferation by upregulating c-Myc and Cyclin D1 expression, as well as participated in mediating IGF2BP1-induced osteoblast activity under mechanical unloading. Notably, Melatonin (MT) might participate in the regulation of the IGF2BP1/LEF1 axis, thereby regulating the proliferation of osteoblasts and bone formation. Collectively, this study revealed a new insight into the regulation of the MT/IGF2BP1/LEF1 pathway in the process of unloading-induced bone loss, which could potentially contribute to establishing therapeutic strategies for disuse osteoporosis.