Suppression of Bone Formation by Osteoclastic Expression of Semaphorin 4D

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2011 Oct 25

PMID 22019888

Citations 211

Authors

Takako Negishi-Koga

Masahiro Shinohara

Noriko Komatsu

Haruhiko Bito

Tatsuhiko Kodama

Roland H Friedel

Hiroshi Takayanagi

Affiliations

Soon will be listed here.

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.

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