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Regulation of osteoclast differentiation and function by the CaMK-CREB pathway

Nature Medicine volume 12, pages 1410–1416 (2006)Cite this article

Abstract

Calcium (Ca2+) signaling is essential for a variety of cellular responses and higher biological functions. Ca2+/calmodulin-dependent kinases (CaMKs) and the phosphatase calcineurin activate distinct downstream pathways that are mediated by the transcription factors cAMP response element (CRE)-binding protein (CREB) and nuclear factor of activated T cells (NFAT), respectively1. The importance of the calcineurin-NFAT pathway in bone metabolism has been demonstrated in osteoclasts, osteoblasts and chondrocytes2,3,4,5. However, the contribution of the CaMK-CREB pathway is poorly understood, partly because of the difficulty of dissecting the functions of homologous family members6,7,8. Here we show that the CaMKIV-CREB pathway is crucial for osteoclast differentiation and function. Pharmacological inhibition of CaMKs as well as the genetic ablation of Camk4 reduced CREB phosphorylation and downregulated the expression of c-Fos, which is required for the induction of NFATc1 (the master transcription factor for osteoclastogenesis2,3) that is activated by receptor activator of NF-κB ligand (RANKL). Furthermore, CREB together with NFATc1 induced the expression of specific genes expressed by differentiated osteoclasts. Thus, the CaMK-CREB pathway biphasically functions to regulate the transcriptional program of osteoclastic bone resorption, by not only enhancing induction of NFATc1 but also facilitating NFATc1-dependent gene regulation once its expression is induced. This provides a molecular basis for a new therapeutic strategy for bone diseases.

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Figure 1: Contribution of CaMKs in RANKL-induced osteoclastogenesis.
Figure 2: Impairment of osteoclast differentiation in Camk4−/− mice under physiological and pathological conditions.
Figure 3: CaMKIV-mediated CREB activation is required for the induction of c-Fos and NFATc1 by RANKL.
Figure 4: Regulation of osteoclast activity by the CaMK-CREB pathway and therapeutic implications.

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Acknowledgements

We are grateful to M.A. Brown (Northwestern University Feinberg School of Medicine), T. Kitamura (Institute of Medical Science, University of Tokyo), R.A. Maurer (Oregon Health & Science University,), T. Miyakawa (Graduate School of Medicine, Kyoto University), N. Nozaki (Kanagawa Dental College), G.D. Roodman (University of Pittsburgh), M. Montminy (Salk Institute for Biological Studies), V. See (Université Louis Pasteur), C. Vinson (National Cancer Institute), Seikagaku Corporation and the RNAi Co. Ltd. for providing materials. We also thank J. Taka, Y. Suzuki, H. Murayama, H. Saito, M. Asagiri, M. Shinohara, T. Koga, H.J. Gober, T. Kunigami, Y. Kim, U. Sato and I. Takayanagi for technical assistance and discussion. This work was supported in part by the Solution Oriented Research for Science and Technology (SORST) program of the Japan Science and Technology Agency (JST); a Grant-in-Aid for Creative Scientific Research from the Japan Society for the Promotion of Science (JSPS); grants for the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT); grants for the 21st Century Center of Excellence program from MEXT; Grants-in Aid for Scientific Research from MEXT; Health Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan; and grants from the Naito Foundation, Suzuken Memorial Foundation, Uehara Memorial Foundation, Kato Memorial Bioscience Foundation, Cell Science Research Foundation and the Nakatomi Foundation.

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Author notes

  1. Kojiro Sato and Ayako Suematsu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University,

    Kojiro Sato, Ayako Suematsu, Tomoki Nakashima & Hiroshi Takayanagi

  2. Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Yushima 1-5-45, Bunkyo-ku, 113-8549, Tokyo, Japan

    Kojiro Sato, Ayako Suematsu, Tomoki Nakashima & Hiroshi Takayanagi

  3. Department of Neurochemistry, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, 113-0033, Tokyo, Japan

    Sayaka Takemoto-Kimura & Haruhiko Bito

  4. Department of Hard Tissue Engineering, Section of Pharmacology, Graduate School, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, 113-8549, Tokyo, Japan

    Kazuhiro Aoki & Keiichi Ohya

  5. Department of Human Pathology, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, 113-0033, Tokyo, Japan

    Yasuyuki Morishita

  6. Department of Innovative Surgery, National Center for Child Health and Development, Okura 2-10-1, Setagaya-ku, 157-8535, Tokyo, Japan

    Hiroshi Asahara

  7. Department of Oral Pathology, Graduate School, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, 113-8549, Tokyo, Japan

    Akira Yamaguchi

  8. Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo 4-1, Aoba-ku, 980-8575, Sendai, Japan

    Toshiyuki Takai

  9. Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Komaba 4-6-1, Meguro-ku, 153-8904, Tokyo, Japan

    Tatsuhiko Kodama

  10. Division of Immunology, Department of Pediatrics, Allergy and Rheumatology, David Geffen School of Medicine at the University of California at Los Angeles, MDCC 12-430, 10833 Le Conte Avenue, Los Angeles, 90095-1752, California, USA

    Talal A Chatila

  11. Solution Oriented Research for Science and Technology (SORST), Japan Science and Technology Agency (JST), Honcho 4-1-8, Kawaguchi, 332-0012, Saitama, Japan

    Haruhiko Bito & Hiroshi Takayanagi

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  1. Kojiro Sato
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Contributions

K.S. and A.S. contributed equally to the manuscript by conducting most of the in vivo and in vitro experiments and by cooperating in the preparation of the manuscript. T.N. supported the in vivo and in vitro experiments, conducted the data analyses and contributed to the manuscript preparation. S.T.-K. and H.B. prepared the plasmids and provided advice on project planning, data interpretation and manuscript preparation. K.A. and K.O. supported the in vivo experiments. Y.M. and A.Y. conducted the histopathological analyses. H.A. prepared the plasmids and contributed to the data analyses. T.T. and T.A.C. generated the genetically modified mice and contributed to the data analyses. T.K. conducted the GeneChip experiments and data analyses. H.T. designed and supervised the project, and wrote the manuscript.

Corresponding author

Correspondence to Hiroshi Takayanagi.

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Sato, K., Suematsu, A., Nakashima, T. et al. Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med 12, 1410–1416 (2006). https://doi.org/10.1038/nm1515

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