Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts

Takayanagi, Hiroshi; Kim, Sunhwa; Koga, Takako; Nishina, Hiroshi; Isshiki, Masashi; Yoshida, Hiroki; Saiura, Akio; Isobe, Miho; Yokochi, Taeko; Inoue, Jun-ichiro; Wagner, Erwin F.; Mak, Tak W.; Kodama, Tatsuhiko; Taniguchi, Tadatsugu

Affiliations

¹Department of Immunology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan

²PRESTO, Japan Science and Technology Corporation (JST), Honcho 4-1-8, Kawaguchi, Saitama 332-0012, Japan

³Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan

⁴Department of Nephrology and Endocrinology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan

⁵Department of Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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

⁷Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

⁸Research Institute of Molecular Pathology (IMP), Dr. Bohr Gasse 7, A-1030 Vienna, Austria

⁹Advanced Medical Discovery Institute and Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada

Abstract

Signaling by RANKL is essential for terminal differentiation of monocytes/macrophages into osteoclasts. The TRAF6 and c-Fos signaling pathways both play important roles downstream of RANKL. We show here that RANKL selectively induces NFATc1 expression via these two pathways. RANKL also evokes Ca2+ oscillations that lead to calcineurin-mediated activation of NFATc1, and therefore triggers a sustained NFATc1-dependent transcriptional program during osteoclast differentiation. We also show that NFATc1-deficient embryonic stem cells fail to differentiate into osteoclasts in response to RANKL stimulation, and that ectopic expression of NFATc1 causes precursor cells to undergo efficient differentiation without RANKL signaling. Thus, NFATc1 may represent a master switch for regulating terminal differentiation of osteoclasts, functioning downstream of RANKL.

Links

DOI: 10.1016/S1534-5807(02)00369-6

PubMed: 12479813

WoS: 000179756100016

History

Received: 2002-08-28

Revised: 2002-11-11

Cited Works (7)

Year	Entry
2002	Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell. April 2002;2(4):389-406.
1999	Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. June 1999;20(3):345-357.
1998	Lacey DL, Timms E, Tan H-L, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian Y-X, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. April 17, 1998;93(2):165-176.
2000	Teitelbaum SL. Bone resorption by osteoclasts. Science. September 1, 2000;289(5484):1504-1508.
1999	Kong Y-Y, Yoshida H, Sarosi I, Tan H-L, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. January 28, 1999;397(6717):315-323.
2000	Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. April 2000;21(2):115-137.
1990	Yoshida H, Hayashi S-I, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa S-I. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature. May 31, 1990;345(6274):442-444.

Cited By (31)

Year	Entry
2006	Robling AG, Castillo AB, Turner CH. Biomechanical and molecular regulation of bone remodeling. Annu Rev Biomed Eng. 2006;8:455-498.
2008	Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys. May 15, 2008;473(2):139-146.
2007	Asagiri M, Takayanagi H. The molecular understanding of osteoclast differentiation. Bone. February 2007;40(2):251-264.
2020	Yu J, Canalis E. Notch and the regulation of osteoclast differentiation and function. Bone. September 2020;138:115474.
2020	Yamakawa T, Okamatsu N, Ishikawa K, Kiyohara S, Handa K, Hayashi E, Sakai N, Karakawa A, Chatani M, Tsuji M, Inagaki K, Kiuchi Y, Negishi-Koga T, Takami M. Novel gene Merlot inhibits differentiation and promotes apoptosis of osteoclasts. Bone. September 2020;138:115494.
2020	Blixt N, Norton A, Zhang A, Aparicio C, Prasad H, Gopalakrishnan R, Jensen ED, Mansky KC. Loss of myocyte enhancer factor 2 expression in osteoclasts leads to opposing skeletal phenotypes. Bone. September 2020;138:115466.
2021	Schreuder WH, van der Wal JE, Lange J, van den Berg H. Multiple versus solitary giant cell lesions of the jaw: similar or distinct entities? Bone. August 2021;149:115935.
2022	Zhao Y, Hao X, Li Z, Feng X, Katz J, Michalek SM, Jiang H, Zhang P. Role of chromatin modulator Dpy30 in osteoclast differentiation and function. Bone. June 2022;159:116379.
2022	Takegahara N, Kim H, Choi Y. RANKL biology. Bone. June 2022;159:116353.
2022	Canalis E, Yee SP, Economides AN, Schilling L, Yu J. Induction of a NOTCH3 Lehman syndrome mutation in osteocytes causes osteopenia in male C57BL/6J mice. Bone. September 2022;162:116476.
2022	Elson A, Anuj A, Barnea-Zohar M, Reuven N. The origins and formation of bone-resorbing osteoclasts. Bone. November 2022;164:116538.
2023	Burciaga SD, Saavedra F, Fischer L, Johnstone K, Jensen ED. Protein kinase D3 conditional knockout impairs osteoclast formation and increases trabecular bone volume in male mice. Bone. July 2023;172:116759.
2020	Mira-Pascual L, Patlaka C, Desai S, Paulie S, Näreoja T, Lång P, Andersson G. A novel sandwich ELISA for tartrate-resistant acid phosphatase 5a and 5b protein reveals that both isoforms are secreted by differentiating osteoclasts and correlate to the type I collagen degradation marker CTX-I in vivo and in vitro. Calcif Tiss Int. February 2020;106(2):194-207.
2020	Klein S, Mentrup B, Timmen M, Sherwood J, Lindemann O, Fobker M, Kronenberg D, Pap T, Raschke MJ, Stange R. Modulation of transient receptor potential channels 3 and 6 regulates osteoclast function with impact on trabecular bone loss. Calcif Tiss Int. June 2020;106(6):655-664.
2021	Takafuji Y, Tatsumi K, Kawao N, Okada K, Muratani M, Kaji H. MicroRNA-196a-5p in extracellular vesicles secreted from myoblasts suppresses osteoclast-like cell formation in mouse cells. Calcif Tiss Int. March 2021;108(3):364-376.
2006	Zhao C, Irie N, Takada Y, Shimoda K, Miyamoto T, Nishiwaki T, Suda T, Matsuo K. Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab. August 2006;4(2):111-121.
2010	Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem. August 13, 2010;285(33):25103-25108.
2019	Li Y, Shi Z, Jules J, Chen S, Kesterson RA, Zhao D, Zhang P, Feng X. Specific RANK cytoplasmic motifs drive osteoclastogenesis. J Bone Miner Res. October 2019;34(10):1938-1951.
2020	Wang Q, Chen D, Jin H, Ye Z, Wang C, Chen K, Kuek V, Xu K, Qiu H, Chen P, Song D, Zhao J, Liu Q, Davis RA, Song F, Xu J. Hymenialdisine: a marine natural product that acts on both osteoblasts and osteoclasts and prevents estrogen‐dependent bone loss in mice. J Bone Miner Res. August 2020;35(8):1582-1596.
2022	Kim HJ, Ryu K-Y, Kim Y-G, Kim MO, Lee JH, Song M-K, Youn Y-J, Pokhrel NK, Kim S-H, Kim J-Y, Jung H-J, Kim W-S, Hong C-W, Kim H-H, Lee Y. Myeloid-specific PTP1B deficiency attenuates inflammation-induced and ovariectomy-induced bone loss in mice by inhibiting osteoclastogenesis. J Bone Miner Res. March 2022;37(3):505-514.
2022	Li H, Wang X, Chen E, Liu X, Ma X, Miao C, Tian Z, Dong R, Hu Y. Introduction of a Cys360Tyr mutation in ANO5 creates a mouse model for gnathodiaphyseal dysplasia. J Bone Miner Res. 2022;37(3):515-530.
2003	Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. August 2003;4(8):638-649.
2003	Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. May 15, 2003;423(6937):337-342.
2015	Scully N. Differentiation of Osteoblasts to Osteocytes in 3D Type I Collagen Gels: A Novel Tool to Study Osteocyte Responses to Mechanical Loading [PhD thesis]. Cardiff, UK: Cardiff University; April 2015.
2014	Lee HG. Innate Immune-Like Function of Osteogenic Cells and Their Effects on Inflammatory Osteolysis [PhD thesis]. Columbia University; 2014.
2011	Linares GR. Novel Molecules That Regulate Bone Formation and Bone Resorption [PhD thesis]. Loma Linda University; June 2011.
2014	Alshbool FZ. The Role of Claudins in Bone Metabolism [PhD thesis]. Loma Linda University; December 2014.
2013	Newa M. Antibody Mediated “Universal” Osteoclast Targeting Platform [PhD thesis]. Edmonton, AB: University of Alberta; 2013.
2019	Wong S-W. The Role of Autophagy Machinery in Osteoclast Disease Pathogenesis [PhD thesis]. University of North Carolina at Chapel Hill; 2019.
2022	Nandi S. HRAS GTPase, a Novel Regulator of Bone Homeostasis: Understanding the Cellular Base of Bone Loss in Costello Syndrome [PhD thesis]. University of Ulm; 2022.
2019	Putnam NE. Innate Immunity and Bone Remodeling During Staphylococcus Aureus Osteomyelitis [PhD thesis]. Nashville, TN: Vanderbilt University; June 30, 2019.