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

Takayanagi, Hiroshi<sup>1,2</sup>; Kim, Sunhwa<sup>1</sup>; Koga, Takako<sup>1,2</sup>; Nishina, Hiroshi<sup>3</sup>; Isshiki, Masashi<sup>4</sup>; Yoshida, Hiroki<sup>2,5</sup>; Saiura, Akio<sup>6</sup>; Isobe, Miho<sup>1,2</sup>; Yokochi, Taeko<sup>1</sup>; Inoue, Jun-ichiro<sup>7</sup>; Wagner, Erwin F.<sup>8</sup>; Mak, Tak W.<sup>9</sup>; Kodama, Tatsuhiko<sup>6</sup>; Taniguchi, Tadatsugu<sup>1</sup>

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

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