biostudies-literatureWille ADeutsche ForschungsgesellschaftDeutsche ForschungsgemeinschaftElse Kröner-Fresenius-Stiftung357-372https://www.ebi.ac.uk/biostudies/studies/S-EPMC11240155biostudies-literatureUnknown39(3)Sphingosine-1-phosphate (S1P) plays multiple roles in bone metabolism and regeneration. Here, we have identified a novel S1P-regulated osteoanabolic mechanism functionally connecting osteoblasts (OBs) to the highly specialized bone vasculature. We demonstrate that S1P/S1PR3 signaling in OBs stimulates vascular endothelial growth factor a (VEGFa) expression and secretion to promote bone growth in an autocrine and boost osteogenic H-type differentiation of bone marrow endothelial cells in a paracrine manner. VEGFa-neutralizing antibodies and VEGF receptor inhibition by axitinib abrogated OB growth in vitro and bone formation in male C57BL/6J in vivo following S1P stimulation and S1P lyase inhibition, respectively. Pharmacological S1PR3 inhibition and genetic S1PR3 deficiency suppressed VEGFaJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral ResearchSphingosine-1-phosphate promotes osteogenesis by stimulating osteoblast growth and neovascularization in a vascular endothelial growth factor-dependent manner.PMC11240155LE 940/8-2BE 4169/8-2GRK2098DFG- INST 208/746-1 FUGGThomas NKeul PDeister-Jonas Jvon Wnuck Lipinski KSchroder NHNowak MKLevkau BWille AWeske SWollnitzke PBehr BfalseSphingosine-1-phosphate promotes osteogenesis by stimulating osteoblast growth and neovascularization in a vascular endothelial growth factor-dependent manner.Sphingosine-1-phosphate (S1P) plays multiple roles in bone metabolism and regeneration. Here, we have identified a novel S1P-regulated osteoanabolic mechanism functionally connecting osteoblasts (OBs) to the highly specialized bone vasculature. We demonstrate that S1P/S1PR3 signaling in OBs stimulates vascular endothelial growth factor a (VEGFa) expression and secretion to promote bone growth in an autocrine and boost osteogenic H-type differentiation of bone marrow endothelial cells in a paracrine manner. VEGFa-neutralizing antibodies and VEGF receptor inhibition by axitinib abrogated OB growth in vitro and bone formation in male C57BL/6J in vivo following S1P stimulation and S1P lyase inhibition, respectively. Pharmacological S1PR3 inhibition and genetic S1PR3 deficiency suppressed VEGFa2024-01-01T00:00:00Z2024 Apr2025-04-26T14:11:50.046Z2025-04-06T14:31:01.811ZS-EPMC112401553847773810.1093/jbmr/zjae006