Journal Article

Targeting skeletal endothelium to ameliorate bone loss

Debnath, Shawon, Shin, Dong Yeon, Shim, Jae-Hyuck, Glimcher, Laurie H., Yang, Xu, Kermani, Pouneh, Bostrom, Mathias P., Zhang, Yi, Xu, Ren, Lalani, Sarfaraz, Liu, Yifang, Di Lorenzo, Annarita, Butler, Jason M., Yallowitz, Alisha, Zhao, Baohong, Qin, An, Dong, Han, Poulos, Michael G., Li, Na, Greenblatt, Matthew B., Inoue, Kazuki, Zhang, Chao, Wach, Amanda, Ji, Gang, Wu, Zhuhao, Kim, Jung-Min

2018

Overview

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 osteoblasts 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. Recombinant SLIT3 represents a new mechanistic approach to treating osteoporosis by increasing skeletal CD31 hi EMCN hi vascular endothelium.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/136/815 / 631/136/818 / 692/699/2743/316/801 / Animals / Biocompatibility / Biomedical and Life Sciences / Biomedical materials / Biomedicine / Bone and Bones - diagnostic imaging / Bone and Bones - drug effects / Bone and Bones - pathology / Bone density / Bone growth / Bone healing / Bone loss / Bone Marrow Cells - drug effects / Bone Marrow Cells - metabolism / Bone mass / Bone Resorption - diagnostic imaging / Bone Resorption - pathology / Cancer Research / Care and treatment / Disease Models, Animal / DNA-Binding Proteins - deficiency / DNA-Binding Proteins - metabolism / Endothelium / Endothelium - drug effects / Endothelium - pathology / Fracture Healing - drug effects / Fracture repair / Fractures / Fractures (Injuries) / Gene mutation / Genetic aspects / Genetic research / Healing / Health aspects / Hormone replacement therapy / Humans / Infectious Diseases / Membrane Proteins - metabolism / Metabolic Diseases / Mice, Inbred BALB C / Mice, Inbred C57BL / Molecular Medicine / Neovascularization, Physiologic - drug effects / Nerve Tissue Proteins - metabolism / Neurosciences / Osteoblasts / Osteoblasts - drug effects / Osteoblasts - metabolism / Osteoblasts - pathology / Osteogenesis / Osteogenesis - drug effects / Osteopenia / Osteoporosis / Osteoporosis, Postmenopausal - drug therapy / Osteoporosis, Postmenopausal - pathology / Ovariectomy / Phenotypes / Platelet Endothelial Cell Adhesion Molecule-1 - metabolism / Post-menopause / Postmenopausal women / Receptors, Immunologic - metabolism / Recombinant Proteins - administration & dosage / Recombinant Proteins - pharmacology / Recombinant Proteins - therapeutic use / Repair / Roundabout Proteins / Sialoglycoproteins - metabolism