Suppression of bone formation by osteoclastic expression of semaphorin 4D

The holy grail in the bone field is the identification of a pharmacological compound that promotes bone growth during osteoporosis. Hiroshi Takayanagi and his colleagues take a step forward in that direction by showing that osteoclast-mediated expression of semaphorin D inhibits osteoblast different...

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Veröffentlicht in:Nature medicine 2011-11, Vol.17 (11), p.1473-1480
Hauptverfasser: Negishi-Koga, Takako, Shinohara, Masahiro, Komatsu, Noriko, Bito, Haruhiko, Kodama, Tatsuhiko, Friedel, Roland H, Takayanagi, Hiroshi
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container_end_page 1480
container_issue 11
container_start_page 1473
container_title Nature medicine
container_volume 17
creator Negishi-Koga, Takako
Shinohara, Masahiro
Komatsu, Noriko
Bito, Haruhiko
Kodama, Tatsuhiko
Friedel, Roland H
Takayanagi, Hiroshi
description The holy grail in the bone field is the identification of a pharmacological compound that promotes bone growth during osteoporosis. Hiroshi Takayanagi and his colleagues take a step forward in that direction by showing that osteoclast-mediated expression of semaphorin D inhibits osteoblast differentiation and that, by inhibiting this pathway with a blocking antibody, they could prevent bone loss in a mouse model of osteoporosis. 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.
doi_str_mv 10.1038/nm.2489
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Hiroshi Takayanagi and his colleagues take a step forward in that direction by showing that osteoclast-mediated expression of semaphorin D inhibits osteoblast differentiation and that, by inhibiting this pathway with a blocking antibody, they could prevent bone loss in a mouse model of osteoporosis. 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. 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subjects 631/154/51/1568
631/208/721
692/698/690/797
692/699/1670/801
Animals
Antibodies - therapeutic use
Antigens, CD - genetics
Antigens, CD - metabolism
Biomedical and Life Sciences
Biomedicine
Bone Resorption - drug therapy
Bone Resorption - metabolism
Bones
Cancer Research
Cell Differentiation
Cell Movement
Cells, Cultured
Development and progression
Drug therapy
Drugs
Female
Femur - anatomy & histology
Femur - pathology
Genetic aspects
Growth
Humans
Infectious Diseases
Metabolic Diseases
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Medicine
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neurosciences
Orthopedics
Osteoclasts - cytology
Osteoclasts - metabolism
Osteogenesis - physiology
Osteoporosis
Osteoporosis - drug therapy
Osteoporosis - pathology
Pharmacology
Physiological aspects
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
rhoA GTP-Binding Protein - genetics
rhoA GTP-Binding Protein - metabolism
Semaphorins
Semaphorins - genetics
Semaphorins - metabolism
Signal Transduction - physiology
title Suppression of bone formation by osteoclastic expression of semaphorin 4D
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