• A Corrigendum to this article was published on 28 August 2013

Abstract

Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance1,2,3,4,5. Previous studies have demonstrated that Sema3a−/− mice have multiple developmental defects due to abnormal neuronal innervations6,7. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3a−/− mice had a low bone mass due to decreased bone formation. However, osteoblast-specific Sema3A-deficient mice (Sema3acol1−/− and Sema3aosx−/− mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons (Sema3asynapsin−/− and Sema3anestin−/− mice) had low bone mass, similar to Sema3a−/− mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin−/− mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin−/− mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a−/− mice, such as olfactory development, were identified in Sema3asynasin−/− mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a−/− mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. This study demonstrates that Sema3A regulates bone remodelling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts.

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Acknowledgements

We thank M. Taniguchi and G. Karsenty for discussions; F. Suto and H. Fujisawa for Plxna4−/− mice; M. Ukegawa, H. Inose, M. Iwata, S. Ohba, T. Hara and G. Itai for technical assistance. This work was supported by the Funding Program for Next Generation World-Leading Researchers (NEXT Program) to S.T., a grant-in-aid for scientific research from the Japan Society for the Promotion of Science to S.T. and T.F., and grants from the National Institute of Neurological Disorders and Stroke (NS065048) to Y.Y.

Author information

Author notes

    • Toru Fukuda
    • , Shu Takeda
    •  & Ren Xu

    These authors equally contributed to this work.

Affiliations

  1. Department of Internal Medicine, School of Medicine, Keio University, Shinanomachi 35, Shinjyuku-ku, Tokyo 160-8582, Japan

    • Toru Fukuda
    • , Shu Takeda
    • , Hiroki Ochi
    •  & Satoko Sunamura
  2. Department of Orthopedic Surgery, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan

    • Ren Xu
    • , Ayako Kimura
    • , Chengshan Ma
    • , Cheng Xu
    • , Koji Fujita
    • , Kenichi Shinomiya
    • , Takashi Hirai
    • , Yoshinori Asou
    • , Mitsuhiro Enomoto
    •  & Atsushi Okawa
  3. Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan

    • Ren Xu
    • , Chengshan Ma
    • , Cheng Xu
    • , Koji Fujita
    •  & Atsushi Okawa
  4. Department of Oral and Maxillofacial Surgery, Saitama Medical University, Morohongo 38, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan

    • Tsuyoshi Sato
  5. Department of Physiology, School of Medicine, Keio University, Shinanomachi 35, Shinjyuku-ku, Tokyo 160-8582, Japan

    • Shinsuke Shibata
    •  & Hideyuki Okano
  6. Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA

    • Yutaka Yoshida
    •  & Zirong Gu
  7. Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan

    • Ayako Kimura
  8. Section of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Keio University, Shinanomachi 35, Shinjyuku-ku, Tokyo 160-8582, Japan

    • Waka Bando
    •  & Hiroshi Itoh

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Contributions

T.F. conducted most of the experiments. R.X., H. Ochi, A.K., Z.G., Y.Y., C.M., C.X., T.H., Y.A. and M.E. conducted mice analyses. T.S., K.F., W.B. and S. Sunamura conducted in vitro experiments. S. Shibata and H. Okano generated mutant mice. A.O., H.I. and K.S. discussed the project. S.T. wrote most of the manuscript. S.T. designed and supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Shu Takeda.

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https://doi.org/10.1038/nature12115

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