Targeting skeletal endothelium to ameliorate bone loss. Academic Article uri icon

Overview

abstract

  • Recent studies have identified a specialized subset of CD31hiendomucinhi (CD31hiEMCNhi) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31hiEMCNhi 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 CD31hiEMCNhi endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31hiEMCNhi 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 CD31hiEMCNhi 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.

publication date

  • May 21, 2018

Research

keywords

  • Bone Resorption
  • Bone and Bones
  • Endothelium

Identity

PubMed Central ID

  • PMC5992080

Scopus Document Identifier

  • 85047216276

Digital Object Identifier (DOI)

  • 10.1038/s41591-018-0020-z

PubMed ID

  • 29785024

Additional Document Info

volume

  • 24

issue

  • 6