Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nature Rev. Immunol. 7, 292–304 (2007)

    Article  CAS  Google Scholar 

  2. Elefteriou, F. Regulation of bone remodeling by the central and peripheral nervous system. Arch. Biochem. Biophys. 473, 231–236 (2008)

    Article  CAS  Google Scholar 

  3. Seeman, E. & Delmas, P. D. Bone quality–the material and structural basis of bone strength and fragility. N. Engl. J. Med. 354, 2250–2261 (2006)

    Article  CAS  Google Scholar 

  4. Teitelbaum, S. L. & Ross, F. P. Genetic regulation of osteoclast development and function. Nature Rev. Genet. 4, 638–649 (2003)

    Article  CAS  Google Scholar 

  5. Martin, T. J. & Sims, N. Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol. Med. 11, 76–81 (2005)

    Article  CAS  Google Scholar 

  6. Lewiecki, E. M. New targets for intervention in the treatment of postmenopausal osteoporosis. Nature Rev. Rheumatol. 7, 631–638 (2011)

    Article  CAS  Google Scholar 

  7. Rachner, T. D., Khosla, S. & Hofbauer, L. C. Osteoporosis: now and the future. Lancet 377, 1276–1287 (2011)

    Article  CAS  Google Scholar 

  8. Reid, I. R. et al. Effects of denosumab on bone histomorphometry: the FREEDOM and STAND studies. J. Bone Miner. Res. 25, 2256–2265 (2010)

    Article  CAS  Google Scholar 

  9. Odvina, C. V. et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J. Clin. Endocrinol. Metab. 90, 1294–1301 (2005)

    Article  CAS  Google Scholar 

  10. Suda, T. et al. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr. Rev. 20, 345–357 (1999)

    Article  CAS  Google Scholar 

  11. Nakashima, T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nature Med. 17, 1231–1234 (2011)

    Article  CAS  Google Scholar 

  12. Xiong, J. et al. Matrix-embedded cells control osteoclast formation. Nature Med. 17, 1235–1241 (2011)

    Article  CAS  Google Scholar 

  13. Simonet, W. S. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997)

    Article  CAS  Google Scholar 

  14. Luo, Y., Raible, D. & Raper, J. A. Collapsin: A protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75, 217–227 (1993)

    Article  CAS  Google Scholar 

  15. Tran, T. S., Kolodkin, A. L. & Bharadwaj, R. Semaphorin regulation of cellular morphology. Annu. Rev. Cell Dev. Biol. 23, 263–292 (2007)

    Article  CAS  Google Scholar 

  16. Negishi-Koga, T. et al. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nature Med. 17, 1473–1480 (2011)

    Article  CAS  Google Scholar 

  17. Takegahara, N. et al. Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nature Cell Biol. 8, 615–622 (2006)

    Article  CAS  Google Scholar 

  18. Matsuo, K. & Irie, N. Osteoclast-osteoblast communication. Arch. Biochem. Biophys. 473, 201–209 (2008)

    Article  CAS  Google Scholar 

  19. Taniguchi, M. et al. Disruption of semaphorin III/D gene causes severe abnormality in peripheral nerve projection. Neuron 19, 519–530 (1997)

    Article  CAS  Google Scholar 

  20. Gomez, C. et al. Expression of Semaphorin-3A and its receptors in endochondral ossification: potential role in skeletal development and innervation. Dev. Dyn. 234, 393–403 (2005)

    Article  CAS  Google Scholar 

  21. Behar, O., Golden, J. A., Mashimo, H., Schoen, F. J. & Fishman, M. C. Semaphorin III is needed for normal patterning and growth of nerves, bones and heart. Nature 383, 525–528 (1996)

    Article  ADS  CAS  Google Scholar 

  22. Jacquin, C., Gran, D. E., Lee, S. K., Lorenzo, J. A. & Aguila, H. L. Identification of multiple osteoclast precursor populations in murine bone marrow. J. Bone Miner. Res. 21, 67–77 (2006)

    Article  Google Scholar 

  23. Neufeld, G. & Kessler, O. The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nature Rev. Cancer 8, 632–645 (2008)

    Article  CAS  Google Scholar 

  24. Gu, C. et al. Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev. Cell 5, 45–57 (2003)

    Article  CAS  Google Scholar 

  25. Ashburner, B. P., Westerheide, S. D. & Baldwin, A. S., Jr The p65 (RelA) subunit of NF-κB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol. Cell. Biol. 21, 7065–7077 (2001)

    Article  CAS  Google Scholar 

  26. Takayanagi, H. et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell 3, 889–901 (2002)

    Article  CAS  Google Scholar 

  27. Koga, T. et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758–763 (2004)

    Article  ADS  CAS  Google Scholar 

  28. Takahashi, T. & Strittmatter, S. M. Plexina1 autoinhibition by the plexin sema domain. Neuron 29, 429–439 (2001)

    Article  CAS  Google Scholar 

  29. Narazaki, M. & Tosato, G. Ligand-induced internalization selects use of common receptor neuropilin-1 by VEGF165 and semaphorin3A. Blood 107, 3892–3901 (2006)

    Article  CAS  Google Scholar 

  30. Nishikawa, K. et al. Maf promotes osteoblast differentiation in mice by mediating the age-related switch in mesenchymal cell differentiation. J. Clin. Invest. 120, 3455–3465 (2010)

    Article  CAS  Google Scholar 

  31. Gimble, J. M., Zvonic, S., Floyd, Z. E., Kassem, M. & Nuttall, M. E. Playing with bone and fat. J. Cell. Biochem. 98, 251–266 (2006)

    Article  CAS  Google Scholar 

  32. Krishnan, V., Bryant, H. U. & Macdougald, O. A. Regulation of bone mass by Wnt signaling. J. Clin. Invest. 116, 1202–1209 (2006)

    Article  CAS  Google Scholar 

  33. Takada, I., Kouzmenko, A. P. & Kato, S. Wnt and PPARγ signaling in osteoblastogenesis and adipogenesis. Nature Rev. Rheumatol. 5, 442–447 (2009)

    Article  CAS  Google Scholar 

  34. Toyofuku, T. et al. FARP2 triggers signals for Sema3A-mediated axonal repulsion. Nature Neurosci. 8, 1712–1719 (2005)

    Article  CAS  Google Scholar 

  35. Wu, X. et al. Rac1 activation controls nuclear localization of β-catenin during canonical Wnt signaling. Cell 133, 340–353 (2008)

    Article  CAS  Google Scholar 

  36. Takegahara, N. et al. Integral roles of a guanine nucleotide exchange factor, FARP2, in osteoclast podosome rearrangements. FASEB J. 24, 4782–4792 (2010)

    Article  CAS  Google Scholar 

  37. Nagashima, M. et al. Bisphosphonate (YM529) delays the repair of cortical bone defect after drill-hole injury by reducing terminal differentiation of osteoblasts in the mouse femur. Bone 36, 502–511 (2005)

    Article  CAS  Google Scholar 

  38. Tang, Y. et al. TGF-β1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nature Med. 15, 757–765 (2009)

    Article  ADS  CAS  Google Scholar 

  39. Hayden, J. M., Mohan, S. & Baylink, D. J. The insulin-like growth factor system and the coupling of formation to resorption. Bone 17, S93–S98 (1995)

    Article  Google Scholar 

  40. Kawai, M., Mödder, U. I., Khosla, S. & Rosen, C. J. Emerging therapeutic opportunities for skeletal restoration. Nature Rev. Drug Discov. 10, 141–156 (2011)

    Article  CAS  Google Scholar 

  41. Grigoriadis, A. E. et al. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 266, 443–448 (1994)

    Article  ADS  CAS  Google Scholar 

  42. Asagiri, M. et al. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J. Exp. Med. 202, 1261–1269 (2005)

    Article  CAS  Google Scholar 

  43. Mizuno, A. et al. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem. Biophys. Res. Commun. 247, 610–615 (1998)

    Article  CAS  Google Scholar 

  44. Kaifu, T. et al. Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J. Clin. Invest. 111, 323–332 (2003)

    Article  CAS  Google Scholar 

  45. Hayashi, M. et al. Ly49Q, an ITIM-bearing NK receptor, positively regulates osteoclast differentiation. Biochem. Biophys. Res. Commun. 393, 432–438 (2010)

    Article  CAS  Google Scholar 

  46. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005)

    Article  ADS  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Hiroshi Takayanagi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-10 and Supplementary Table 1. (PDF 10755 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11000

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research