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Evidence for osteocyte regulation of bone homeostasis through RANKL expression

Nature Medicine volume 17, pages 1231–1234 (2011)Cite this article

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Abstract

Osteocytes embedded in bone have been postulated to orchestrate bone homeostasis by regulating both bone-forming osteoblasts and bone-resorbing osteoclasts. We find here that purified osteocytes express a much higher amount of receptor activator of nuclear factor-κB ligand (RANKL) and have a greater capacity to support osteoclastogenesis in vitro than osteoblasts and bone marrow stromal cells. Furthermore, the severe osteopetrotic phenotype that we observe in mice lacking RANKL specifically in osteocytes indicates that osteocytes are the major source of RANKL in bone remodeling in vivo.

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Figure 1: New method of isolating osteocytes and RANKL expression in osteocytes.
Figure 2: Osteopetrotic phenotype in osteocyte-specific Tnfsf11-deficient mice.

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Acknowledgements

We are grateful to J. Miyazaki for providing CAG-CAT-EGFP transgenic mice and U. Möhle-Steinlein for assisting the generation of A9 embryonic stem cells. We thank S. Fukuse, T. Suda-Kayamori, T. Nishioka-Honda, T. Ando, Y. Kunisawa, E. Idrus, K. Nishikawa, H. Inoue, K. Okamoto, T. Negishi-Koga, M. Shinohara, L. Bakiri, Ö. Uluçkan, N. Amizuka, K. Kayamori, A. Yamaguchi and S. Iseki for discussion and assistance. We also thank T. Wada, H. Hara, Y. Nakashima, R. Hanada, T. Hanada, A. Leibbrant, S.J. Cronin, G.G. Neely, N. Joza, J.A. Pospisilik and A. Meixner for technical 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-Aids 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, Nakatomi Foundation, Nagao Memorial Foundation, Kowa Life Science Foundation, Naito Foundation, Ichiro Kanehara Foundation, Senri Life Science Foundation and Astellas Foundation for Research on Metabolic Disorders.

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Authors and Affiliations

  1. Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan

    Tomoki Nakashima, Mikihito Hayashi, Takanobu Fukunaga, Masatsugu Oh-hora & Hiroshi Takayanagi

  2. Japan Science and Technology Agency, Exploratory Research for Advanced Technology Program, Takayanagi Osteonetwork Project, Yushima, Bunkyo-ku, Tokyo, Japan

    Tomoki Nakashima, Mikihito Hayashi & Hiroshi Takayanagi

  3. Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Yushima, Bunkyo-ku, Tokyo, Japan

    Tomoki Nakashima, Mikihito Hayashi, Takanobu Fukunaga, Masatsugu Oh-hora & Hiroshi Takayanagi

  4. Department of Mechanical Engineering, Faculty of Engineering, Kyushu University, Motooka, Nishi-ku, Fukuoka, Japan

    Kosaku Kurata

  5. Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, Texas, USA

    Jian Q Feng

  6. Department of Oral Biology, University of Missouri at Kansas City, Kansas City, Missouri, USA

    Lynda F Bonewald

  7. Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan

    Tatsuhiko Kodama

  8. Department of Biochemistry, The Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge, UK

    Anton Wutz

  9. Genes, Development and Disease Group, Banco Bilbao Vizcaya Argentaria Foundation, Cancer Cell Biology Program, Spanish National Cancer Center, Madrid, Spain

    Erwin F Wagner

  10. Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria

    Josef M Penninger

  11. Center for Orthopaedic Research, School of Surgery, The University of Western Australia, Perth, Australia

    Hiroshi Takayanagi

Authors
  1. Tomoki Nakashima
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  2. Mikihito Hayashi
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  3. Takanobu Fukunaga
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  4. Kosaku Kurata
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  5. Masatsugu Oh-hora
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  6. Jian Q Feng
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  7. Lynda F Bonewald
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  8. Tatsuhiko Kodama
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  9. Anton Wutz
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  10. Erwin F Wagner
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  11. Josef M Penninger
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  12. Hiroshi Takayanagi
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Contributions

T.N. generated conditional knockout mice, performed most of the experiments, interpreted the results and prepared the manuscript. M.H. participated in the in vivo analyses of the mice and prepared the manuscript. T.F. and K.K. performed experiments using the three-dimensional gel-embedded cell culture system and contributed to the osteocyte isolation experiments. M.O. assisted the in vivo analyses of the mice. J.Q.F. and L.F.B. provided Dmp1-Cre deleter mice and advice on project planning and data interpretation. L.F.B. also provided the osteocyte-like cell line MLO-Y4. T.K. conducted the GeneChip analysis. A.W. and E.F.W. generated embryonic stem cells and provided technical help. J.M.P. provided advice on project planning. H.T. directed, supervised the project and wrote the manuscript.

Corresponding author

Correspondence to Hiroshi Takayanagi.

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The authors declare no competing financial interests.

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Supplementary Methods and Supplementary Figures 1–13 (PDF 1568 kb)

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Nakashima, T., Hayashi, M., Fukunaga, T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 17, 1231–1234 (2011). https://doi.org/10.1038/nm.2452

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