Suppression of bone formation by osteoclastic expression of semaphorin 4D

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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Figure 1: Inhibition of bone formation by osteoclast-derived Sema4D.
Figure 2: Plexin-B1 functions as a receptor for Sema4D in osteoblasts.
Figure 3: Inhibition of bone formation by the Sema4D–Plexin-B1–RhoA axis.
Figure 4: Osteoblas-spec st-specific loss of function of Rho GTPase leads to an osteosclerotic phenotype.
Figure 5: The mechanism of Sema4D–Plexin-B1–RhoA-mediated regulation of bone formation.
Figure 6: The bone-increasing effect of Sema4D–Plexin-B1 blockade.

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Acknowledgements

We are grateful to G. Karsenty (Columbia University), K. Kobayashi (Fukushima Medical University School of Medicine), A. Kumanogoh (Osaka University) and T. Kitamura (The University of Tokyo) for kindly providing α(1)I-Cre mice, CAT-RhoA DN mice, recombinant Fc-sema4D protein, and the retrovirus vectors and Plat-E cells, respectively. We also thank E. Sumiya, A. Suematsu, Y. Kunisawa, T. Ando, K. Okamoto, T. Nakashima, M. Oh-hora, M. Hayashi, A. Terashima, Y. Nagai and H. Negishi for discussion and assistance. This work was supported in part by a grant for the Exploratory Research for Advanced Technology, Takayanagi Osteonetwork Project from the Japan Science and Technology Agency, Grant-in-Aid for Young Scientist A, Grant-in-Aid for Challenging Exploratory Research and Grant-in-Aid for JSPS Fellows from the Japan Society for the Promotion of Science, a grant for the Global Center of Excellence Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and grants from the Ichiro Kanehara Foundation, the Uehara Memorial Foundation and the Naito Foundation.

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T.N.-K. performed most of the experiments, interpreted the results and prepared the manuscript. M.S. performed the molecular analysis of the regulation of bone formation by RhoA and contributed to the GTPase analysis and manuscript preparation. N.K. performed the FACS analysis. H.B. generated adenoviruses and contributed to data interpretation. T.K. conducted the GeneChip analysis. R.H.F. generated Plxnb1−/− mice and contributed to data interpretation. H.T. directed the project and wrote the manuscript.

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Correspondence to Hiroshi Takayanagi.

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Negishi-Koga, T., Shinohara, M., Komatsu, N. et al. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat Med 17, 1473–1480 (2011). https://doi.org/10.1038/nm.2489

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