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Osteoprotection by semaphorin 3A

Abstract

The bony skeleton is maintained by local factors that regulate bone-forming osteoblasts and bone-resorbing osteoclasts, in addition to hormonal activity. Osteoprotegerin protects bone by inhibiting osteoclastic bone resorption, but no factor has yet been identified as a local determinant of bone mass that regulates both osteoclasts and osteoblasts. Here we show that semaphorin 3A (Sema3A) exerts an osteoprotective effect by both suppressing osteoclastic bone resorption and increasing osteoblastic bone formation. The binding of Sema3A to neuropilin-1 (Nrp1) inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation by inhibiting the immunoreceptor tyrosine-based activation motif (ITAM) and RhoA signalling pathways. In addition, Sema3A and Nrp1 binding stimulated osteoblast and inhibited adipocyte differentiation through the canonical Wnt/β-catenin signalling pathway. The osteopenic phenotype in Sema3a−/− mice was recapitulated by mice in which the Sema3A-binding site of Nrp1 had been genetically disrupted. Intravenous Sema3A administration in mice increased bone volume and expedited bone regeneration. Thus, Sema3A is a promising new therapeutic agent in bone and joint diseases.

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Figure 1: Identification of Sema3A as an inhibitory factor of osteoclast differentiation.
Figure 2: Sema3a −/− and Nrp1 Sema− mice show a severe low bone mass phenotype.
Figure 3: Inhibition of osteoclast differentiation by Sema3A−Nrp1 signalling.
Figure 4: Impaired osteoblast differentiation and increased adipocyte differentiation in Sema3a −/− and Nrp1 Sema− mice.
Figure 5: Regulation of osteoblast differentiation by Sema3A through canonical Wnt signalling.
Figure 6: Sema3A as a potential bone-increasing agent.

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Acknowledgements

We are grateful to D. D. Ginty and A. L. Kolodkin for providing the Nrp1Sema− knockin mice. We thank Y. Goshima for providing vectors and technical help. We thank A. Yamaguchi, H. Asahara and F. Suto for providing reagents and technical help. We also thank K. Okamoto, T. Negishi-Koga, K. Nishikawa, H. Inoue, T. Suda, T. Ando, Y. Kunisawa, Y. Ogihara and S. Fukuse for discussion and assistance. This work was supported in part by a grant for the Exploratory Research for Advanced Technology Program, the Takayanagi Osteonetwork Project from the Japan Science and Technology Agency; Grant-in-Aid for Young Scientist A from the Japan Society for the Promotion of Science (JSPS); a Grant-in-Aid for Challenging Exploratory Research from the JSPS; grants for the Global Center of Excellence Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and grants from the Tokyo Biochemical Research Foundation, the Life Science Foundation of Japan, Takeda Science Foundation, Uehara Memorial Foundation, Naito Foundation, BMKK RA Research Fund and Astellas Foundation for Research on Metabolic Disorders.

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M.H. performed most of the experiments, interpreted the results and prepared the manuscript. T.N. performed immunohistochemical experiments and provided advice on project planning and data interpretation and prepared the manuscript. M.T. provided technical help. T.K. conducted the GeneChip analysis. A.K. provided advice on project planning and technical help. H.T. directed, supervised the project and wrote the manuscript.

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Correspondence to Hiroshi Takayanagi.

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Hayashi, M., Nakashima, T., Taniguchi, M. et al. Osteoprotection by semaphorin 3A. Nature 485, 69–74 (2012). https://doi.org/10.1038/nature11000

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