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Osteoprotection by semaphorin 3A

Author

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  • Mikihito Hayashi

    (Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan
    Japan Science and Technology Agency, Exploratory Research for Advanced Technology Program, Takayanagi Osteonetwork Project, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan
    Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan)

  • Tomoki Nakashima

    (Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan
    Japan Science and Technology Agency, Exploratory Research for Advanced Technology Program, Takayanagi Osteonetwork Project, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan
    Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan)

  • Masahiko Taniguchi

    (Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo 060-8556, Japan)

  • Tatsuhiko Kodama

    (Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan)

  • Atsushi Kumanogoh

    (Allergy and Rheumatic Diseases, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
    Immunology Frontier Research Center, Osaka University, Yamadaoka 3-1, Suita, Osaka 565-0871, Japan)

  • Hiroshi Takayanagi

    (Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan
    Japan Science and Technology Agency, Exploratory Research for Advanced Technology Program, Takayanagi Osteonetwork Project, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan
    Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan
    Centre for Orthopaedic Research, School of Surgery, The University of Western Australia, Nedlands, Western Australia 6009, Australia)

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.

Suggested Citation

  • Mikihito Hayashi & Tomoki Nakashima & Masahiko Taniguchi & Tatsuhiko Kodama & Atsushi Kumanogoh & Hiroshi Takayanagi, 2012. "Osteoprotection by semaphorin 3A," Nature, Nature, vol. 485(7396), pages 69-74, May.
    • Handle: RePEc:nat:nature:v:485:y:2012:i:7396:d:10.1038_nature11000
    DOI: 10.1038/nature11000
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    Cited by:

    1. Maki Uenaka & Erika Yamashita & Junichi Kikuta & Akito Morimoto & Tomoka Ao & Hiroki Mizuno & Masayuki Furuya & Tetsuo Hasegawa & Hiroyuki Tsukazaki & Takao Sudo & Keizo Nishikawa & Daisuke Okuzaki & , 2022. "Osteoblast-derived vesicles induce a switch from bone-formation to bone-resorption in vivo," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Anhao Liu & Mikihito Hayashi & Yujin Ohsugi & Sayaka Katagiri & Shizuo Akira & Takanori Iwata & Tomoki Nakashima, 2024. "The IL-33/ST2 axis is protective against acute inflammation during the course of periodontitis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Masayuki Tsukasaki & Noriko Komatsu & Takako Negishi-Koga & Nam Cong-Nhat Huynh & Ryunosuke Muro & Yutaro Ando & Yuka Seki & Asuka Terashima & Warunee Pluemsakunthai & Takeshi Nitta & Takashi Nakamura, 2022. "Periosteal stem cells control growth plate stem cells during postnatal skeletal growth," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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