| 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 |
36.13
|
| Times Cited |
242
|
|
WOS Category
|
MEDICINE, RESEARCH & EXPERIMENTAL
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
| Resource |
| Mice |
RBRC01295 |
