Histone lactylation ameliorates postmenopausal osteoporosis by IGF2BP1-dependent SMAD1 stabilization

Epigenetic changes affect the progression of osteoporosis (OP), of which RNA and histone modifications have attracted much attention. Here, we investigated the role of histone lactylation and N6-methyladenosine (m6A) methylation in OP and the molecular mechanism. The OP mouse model was generated by ovariectomy (OVX), and the in vitro study was performed using osteogenic-induced bone marrow mesenchymal stem cells (BMSCs). The results showed that the levels of whole lactylation and H3K18 were decreased in OVX-induced mice and elevated in osteogenic BMSCs. Inhibition of H3K18 lactylation using oxamate promoted bone defect and inhibited osteogenic differentiation of BMSCs, while promotion of H3K18 lactylation using Nala has the opposite results. Then, we found that H3K18 lactylation was enriched in the IGF2BP1 promoter and facilitated the transcription of IGF2BP1. IGF2BP1 overexpression attenuated OVX-induced bone defect, whereas its knockdown inhibited osteogenesis. Moreover, IGF2BP1 recognized the m6A methylation of SMAD1 and enhanced its stability. Overexpression of SMAD1 reversed the inhibition of osteogenesis and bone defect induced by IGF2BP1 silence. In conclusion, histone lactylation alleviates OP through promoting osteogenesis by transcriptionally regulating IGF2BP1, which recognizes m6A methylation of SMAD1. These findings provide new insights into the role of epigenetics in the pathogenesis of OP.