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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References
Takayanagi, H. Nat. Rev. Immunol. 7, 292–304 (2007).
Takahashi, N. et al. Endocrinology 123, 2600–2602 (1988).
Chambers, T.J., Owens, J.M., Hattersley, G., Jat, P.S. & Noble, M.D. Proc. Natl. Acad. Sci. USA 90, 5578–5582 (1993).
Rodan, G.A. & Martin, T.J. Calcif. Tissue Int. 33, 349–351 (1981).
Suda, T. et al. Endocr. Rev. 20, 345–357 (1999).
Kong, Y.Y. et al. Nature 397, 315–323 (1999).
Kim, N., Odgren, P.R., Kim, D.K., Marks, S.C. Jr. & Choi, Y. Proc. Natl. Acad. Sci. USA 97, 10905–10910 (2000).
Bonewald, L.F. J. Bone Miner. Res. 26, 229–238 (2011).
Hanada, R., Hanada, T., Sigl, V., Schramek, D. & Penninger, J.M. J. Mol. Med. 89, 647–656 (2011).
Sobacchi, C. et al. Nat. Genet. 39, 960–962 (2007).
Gu, G., Nars, M., Hentunen, T.A., Metsikko, K. & Vaananen, H.K. Cell Tissue Res. 323, 263–271 (2006).
Kramer, I. et al. Mol. Cell. Biol. 30, 3071–3085 (2010).
Paic, F. et al. Bone 45, 682–692 (2009).
Kawamoto, S. et al. FEBS Lett. 470, 263–268 (2000).
Lu, Y. et al. J. Dent. Res. 86, 320–325 (2007).
Franz-Odendaal, T.A., Hall, B.K. & Witten, P.E. Dev. Dyn. 235, 176–190 (2006).
O'Brien, C.A. et al. PLoS ONE 3, e2942 (2008).
Seeman, E. & Delmas, P.D. N. Engl. J. Med. 354, 2250–2261 (2006).
Martin, T.J. J. Musculoskelet. Neuronal Interact. 4, 243–253 (2004).
Pivonka, P. et al. Bone 43, 249–263 (2008).
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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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.
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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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DOI: https://doi.org/10.1038/nm.2452
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