Targeting skeletal endothelium to ameliorate bone loss.

Abstract

Recent studies have identified a specialized subset of CD31^hiendomucin^hi (CD31^hiEMCN^hi) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31^hiEMCN^hi endothelium levels are coupled to anabolic bone formation. Mice with an osteoblast-specific deletion of Shn3, which have markedly elevated bone formation, demonstrated an increase in CD31^hiEMCN^hi endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31^hiEMCN^hi endothelium, resulted in low bone mass because of impaired bone formation and partially reversed the high bone mass phenotype of Shn3^-/- mice. This coupling between osteoblasts and CD31^hiEMCN^hi endothelium is essential for bone healing, as shown by defective fracture repair in SLIT3-mutant mice and enhanced fracture repair in SHN3-mutant mice. Finally, administration of recombinant SLIT3 both enhanced bone fracture healing and counteracted bone loss in a mouse model of postmenopausal osteoporosis. Thus, drugs that target the SLIT3 pathway may represent a new approach for vascular-targeted osteoanabolic therapy to treat bone loss.