RRC ID 12675
Author Negishi-Koga T, Shinohara M, Komatsu N, Bito H, Kodama T, Friedel RH, Takayanagi H.
Title Suppression of bone formation by osteoclastic expression of semaphorin 4D.
Journal Nat. Med.
Abstract Most of the currently available drugs for osteoporosis inhibit osteoclastic bone resorption; only a few drugs promote osteoblastic bone formation. It is thus becoming increasingly necessary to identify the factors that regulate bone formation. We found that osteoclasts express semaphorin 4D (Sema4D), previously shown to be an axon guidance molecule, which potently inhibits bone formation. The binding of Sema4D to its receptor Plexin-B1 on osteoblasts resulted in the activation of the small GTPase RhoA, which inhibits bone formation by suppressing insulin-like growth factor-1 (IGF-1) signaling and by modulating osteoblast motility. Sema4d-/- mice, Plxnb1-/- mice and mice expressing a dominant-negative RhoA specifically in osteoblasts showed an osteosclerotic phenotype due to augmented bone formation. Notably, Sema4D-specific antibody treatment markedly prevented bone loss in a model of postmenopausal osteoporosis. Thus, Sema4D has emerged as a new therapeutic target for the discovery and development of bone-increasing drugs.
Volume 17(11)
Pages 1473-80
Published 2011-10-23
DOI 10.1038/nm.2489
PII nm.2489
PMID 22019888
MeSH Animals Antibodies / therapeutic use Antigens, CD / genetics Antigens, CD / metabolism* Bone Resorption / drug therapy Bone Resorption / metabolism Cell Differentiation Cell Movement Cells, Cultured Female Femur / anatomy & histology Femur / pathology Humans Mice Mice, Inbred C57BL Mice, Knockout Nerve Tissue Proteins / genetics Nerve Tissue Proteins / metabolism Osteoclasts / cytology Osteoclasts / metabolism* Osteogenesis / physiology* Osteoporosis / drug therapy Osteoporosis / pathology Receptors, Cell Surface / genetics Receptors, Cell Surface / metabolism Semaphorins / genetics Semaphorins / metabolism* Signal Transduction / physiology rhoA GTP-Binding Protein / genetics rhoA GTP-Binding Protein / metabolism
IF 32.621
Times Cited 135
Mice CAT-RhoA DN/4-18