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.
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We thank the many individuals who provided valuable reagents. M.B.G. holds a Career Award for Medical Scientists from the Burroughs Wellcome Foundation and is supported by the Office of the Director of the NIH under award DP5OD021351, a Junior Investigator Award from the Musculoskeletal Transplant Foundation and a March of Dimes Basil O’Connor Award. J.-H.S. is supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH under R01AR068983 and a pilot project program award from UMass Center for Clinical and Translational Science. A.D.L. is supported by NIH/National Heart, Lung, and Blood Institute under R01 HL126913. This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank D. Ballon, B. He, B. -S. Ding and J. McCormick and Citigroup Biomedical Imaging Core, Weill Cornell Microscopy and Image Analysis and Flow Cytometry Core Facilities for technical support.
L.H.G. is on the board of directors of and holds equity in the GlaxoSmithKline and Waters Corporations. She is also a founder of Quentis Pharmaceuticals.
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