Journal
NATURE MEDICINE
Volume 24, Issue 6, Pages 823-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41591-018-0020-z
Keywords
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Funding
- Career Award for Medical Scientists from the Burroughs Wellcome Foundation
- Office of the Director of the NIH [DP5OD021351]
- Musculoskeletal Transplant Foundation
- March of Dimes Basil O'Connor Award
- National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH [R01AR068983]
- pilot project program award from UMass Center for Clinical and Translational Science
- NIH/National Heart, Lung, and Blood Institute [R01 HL126913]
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Recent studies have identified a specialized subset of CD31(hi)endomucin(hi) (CD31(hi)EMCN(hi)) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31(hi)EMCN(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(hi)EMCN(hi) endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31(hi)EMCN(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 osteo-blasts and CD31(hi)EMCN(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.
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