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J. Biol. Chem., Vol. 280, Issue 38, 32905-32913, September 23, 2005

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Contribution of Nuclear Factor of Activated T Cells c1 to the Transcriptional Control of Immunoreceptor Osteoclast-associated Receptor but Not Triggering Receptor Expressed by Myeloid Cells-2 during Osteoclastogenesis^*

Yoonji Kim¶||, Kojiro Sato, Masataka Asagiri, Ikuo Morita||, Kunimichi Soma¶, and Hiroshi Takayanagi1

From the Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, the Solution Oriented Research for Science and Technology Program (SORST), Japan Science and Technology Agency, Saitama 332-0014, and the Center of Excellence (COE) Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo 113-8549, ^¶Orthodontic Science, Department of Orofacial Development and Function, Division of Oral Health Sciences, Graduate School, Tokyo 113-8549, and the ^||Department of Cellular Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan

Bone homeostasis depends on the coordination of osteoclastic bone resorption and osteoblastic bone formation. Receptor activator of NF-B ligand (RANKL) induces osteoclast differentiation through activating a transcriptional program mediated by the key transcription factor nuclear factor of activated T cells (NFAT) c1. Immunoreceptors, including osteoclast-associated receptor (OSCAR) and triggering receptor expressed by myeloid cells (TREM)-2, constitute the co-stimulatory signals required for RANKL-mediated activation of calcium signaling, which leads to the activation of NFATc1. However, it remains unknown whether the expression of immunoreceptors are under the control of NFATc1. Here we demonstrate that the expression of OSCAR, but not that of TREM-2, is up-regulated during osteoclastogenesis and markedly suppressed by the calcineurin inhibitor FK506, suggesting that OSCAR is transcriptionally regulated by NFATc1. NFATc1 expression results in the activation of the OSCAR promoter, which was found to be further enhanced by co-expression of PU.1 and microphthalmia-associated transcription factor (MITF). We further provide evidence that NFATc1 specifically regulates OSCAR by chromatin immunoprecipitation assay and quantification of OSCAR and TREM-2 mRNA in NFATc1^-/- cells. Thus, OSCAR but not TREM-2 is involved in the positive feedback loop of the immunoreceptor-NFATc1 pathway during osteoclastogenesis. Although several immunoreceptors have been identified as co-stimulatory molecules for RANKL, the expression and function are differentially regulated. These mechanisms, possibly together with the delicate regulation of their ligands on osteoblasts, may provide the exquisite machinery for the modulation of osteoclastogenesis in the maintenance of bone homeostasis.

Received for publication, May 27, 2005 , and in revised form, July 18, 2005.

^* This work was supported by SORST program of the Japan Science and Technology Agency, grants for Genome Network Project from Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT), grants for the 21st century COE program, grants-in-aid for Scientific Research from Japan Society for the Promotion of Science, and MEXT, Health Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan, grants from the Mitsubishi Foundation, The Kato Trust for Nambyo Research, the Takeda Science foundation, the Daiwa Securities Health Foundation, The Naito Foundation, the Kowa Life Science Foundation, the Suzuken Memorial Foundation, the Kato Memorial Bioscience Foundation, the Inamori foundation, and the Uehara Memorial Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan. Tel.: 81-3-5803-5471; Fax: 81-3-5803-0192; E-mail: taka.csi{at}tmd.ac.jp.

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