Suppression of bone formation by osteoclastic expression of semaphorin 4D.
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.
Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Takako
T
Negishi-Koga
Masahiro
M
Shinohara
Noriko
N
Komatsu
Haruhiko
H
Bito
Tatsuhiko
T
Kodama
Roland H
RH
Friedel
Hiroshi
H
Takayanagi
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D005260:Female; D005269:Femur / Q000033:anatomy & histology / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D010024:Osteoporosis / Q000188:drug therapy / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D000906:Antibodies; D015703:Antigens, CD; C093224:CD100 antigen; D009419:Nerve Tissue Proteins; C492118:Plxnb1 protein, mouse; D011956:Receptors, Cell Surface; D039961:Semaphorins; D020742:rhoA GTP-Binding Protein