Targeting skeletal endothelium to ameliorate bone loss.

TitleTargeting skeletal endothelium to ameliorate bone loss.
Publication TypeJournal Article
Year of Publication2018
AuthorsXu R, Yallowitz A, Qin A, Wu Z, Shin DYeon, Kim J-M, Debnath S, Ji G, Bostrom MP, Yang X, Zhang C, Dong H, Kermani P, Lalani S, Li N, Liu Y, Poulos MG, Wach A, Zhang Y, Inoue K, Di Lorenzo A, Zhao B, Butler JM, Shim J-H, Glimcher LH, Greenblatt MB
JournalNat Med
Volume24
Issue6
Pagination823-833
Date Published2018 06
ISSN1546-170X
KeywordsAnimals, Bone and Bones, Bone Marrow Cells, Bone Resorption, Disease Models, Animal, DNA-Binding Proteins, Endothelium, Fracture Healing, Humans, Membrane Proteins, Mice, Inbred BALB C, Mice, Inbred C57BL, Neovascularization, Physiologic, Nerve Tissue Proteins, Osteoblasts, Osteogenesis, Osteoporosis, Postmenopausal, Ovariectomy, Platelet Endothelial Cell Adhesion Molecule-1, Receptors, Immunologic, Recombinant Proteins, Sialoglycoproteins
Abstract

Recent studies have identified a specialized subset of CD31endomucin (CD31EMCN) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31EMCN 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 CD31EMCN endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31EMCN 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 CD31EMCN 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.

DOI10.1038/s41591-018-0020-z
Alternate JournalNat Med
PubMed ID29785024
PubMed Central IDPMC5992080
Grant ListR01 AR071463 / AR / NIAMS NIH HHS / United States
R01 AR068970 / AR / NIAMS NIH HHS / United States
DP5 OD021351 / OD / NIH HHS / United States
R01 AR075585 / AR / NIAMS NIH HHS / United States
S10 OD019986 / OD / NIH HHS / United States
R01 HL126913 / HL / NHLBI NIH HHS / United States
R01 AR068983 / AR / NIAMS NIH HHS / United States
Related Faculty: 
Annarita Di Lorenzo, Ph.D. Matthew B. Greenblatt, M.D., Ph.D.

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