CGRP Enhances the Regeneration of Bone Defects by Regulating Bone Marrow Mesenchymal Stem Cells Through Promoting ANGPTL4 Secretion by Bone Blood Vessels

ABSTRACT Bone angiogenesis is important for bone formation and regeneration after bone injury. Endothelial‐derived angiogenic factors are key signal transducers in the bone microenvironment and maintain vascular–osteogenic coupling during bone regeneration. CGRP, a bone sensory neuron‐derived peptide, contributes to bone formation, but the potential mechanism by which it improves bone regeneration via angiogenesis is unclear. Here, we demonstrate that CGRP may contribute to bone repair in the elderly, as human CGRP levels are inversely proportional to age and proportional to bone mass in clinical data and bulk transcriptome data. Based on single‐cell RNA sequencing data and experimental analyses, CGRP is found to promote the angiogenesis of human microvascular endothelial cell line‐1 in vitro through the FAK–AKT–VEGF pathway. CGRP gene deletion in mice reduced bone vascular density and bone mass, and delayed angiogenesis and bone regeneration at the bone defect site. Recombinant CGRP restored bone repair after defect introduction. It also promoted Angptl4 secretion by bone vascular endothelial cells, thereby driving osteogenic differentiation of bone marrow mesenchymal stem cells and enhancing bone regeneration after bone injury. Treatment with recombinant Angptl4 enhanced bone healing in a mouse bone defect model. These integrated analysis reveal the important role and mechanism of CGRP in vascular‐mediated osteogenesis, suggesting a novel therapeutic strategy for promoting bone regeneration.