RNA-binding protein YBX1 promotes Type H vessels dependent bone formation in an m5C-dependent manner

RNA Binding Proteins (RBPs) interact with RNA and ubiquitously regulating RNA transcripts during their life cycle. Previous works showed that RBPs play fundamental roles in the progression of angiogenesis-related diseases. However, the role of RBPs in skeletal endothelium-dependent bone formation and osteogenesis is unclear. Here, we show that RBP-Ybx1 was strongly reduced in bone vasculature from ovariectomy-induced osteoporotic mice. Endothelial cell-specific deletion of Ybx1 impaired CD31 hi EMCN hi endothelium morphology and osteogenesis and resulted in low bone mass, while its overexpression promoted angiogenesis-dependent osteogenesis and ameliorated bone loss in OVX mice. Mechanistically, Ybx1 deletion disrupted CD31, EMCN and BMP4 stability in an m5C-dependent manner and blocked endothelial-derived BMP4 release, thereby inhibiting osteogenic differentiation of BMSCs. Administration of recombinant BMP4 protein promoted osteogenic differentiation of BMSCs and restored impaired bone formation in Ybx1 iΔEC mice. Finally, tail vein injection of CD31-modified PEG-PLGA carrying sciadopitysin, a natural Ybx1 agonist, pharmacologically partially reversed CD31 hi EMCN hi vessels decline and improved the restoration of bone mass both in OVX and aging animals. These findings demonstrated the role of RBP-Ybx1 in angiogenesis-dependent bone formation and provided a novel therapeutic approach for ameliorating aging-related and postmenopausal osteoporosis.