Irisin inhibits adipogenic differentiation of bone marrow mesenchymal stem cells through the SIRT1/RANBP2/FTO signaling axis and protects against osteoporosis

Abnormal bone marrow obesity caused by the conversion of bone marrow mesenchymal stem cells (BMMSCs) from osteoblast to adipocyte differentiation is one of the significant contributors to age and menopause-related osteoporosis (OP) development. Irisin, one of the myokines, has been reported to be involved in skeletal metabolic diseases, providing new insights into the pathogenesis of OP. However, the specific mechanism of irisin in adipogenic differentiation of BMMSCs has not been thoroughly explored. Clinical data from this study confirmed the expression of irisin in OP and its clinical significance. In addition, irisin inhibited adipogenic differentiation of BMMSCs in vitro and reduced bone loss and abnormal bone marrow obesity in ovariectomized (OVX) mice. Mechanistically, SIRT1 was identified as a downstream target of irisin, and activated SIRT1 inhibited the expression of FTO through deacetylating RANBP2, which downregulated the stability and expression of PPARγ. The current study revealed a novel molecular mechanism by which irisin mediated BMMSCs adipogenesis through the SIRT1/RANBP2/FTO signaling axis.