Suppression of bone formation by osteoclastic expression of semaphorin 4D

Takako Negishi-Koga, Masahiro Shinohara, Noriko Komatsu, Haruhiko Bito, Tatsuhiko Kodama, Roland H. Friedel, Hiroshi Takayanagi

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394 Scopus citations


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.

Original languageEnglish
Pages (from-to)1473-1480
Number of pages8
JournalNature Medicine
Issue number11
StatePublished - Nov 2011


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