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¹ Department of Cell Signaling, Graduate School
² Department of Medicine and Rheumatology, Graduate School
³ Department of Cellular Physiological Chemistry, Graduate School
⁴ Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
⁵ Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
⁶ Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
⁷ Laboratory of Recombinant Animals, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
⁸ Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
⁹ Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga City, Saga 849-8501, Japan
¹⁰ Research Institute of Molecular Pathology, A-1030 Vienna, Austria
¹¹ Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada
¹² Department of Medical Biophysics, Advanced Medical Discovery Institute, University of Toronto, Toronto, Ontario M5G 2C1, Canada
¹³ Department of Molecular Pathology, Institute of Pathology, University of Wüerzburg, D-97080 Wüerzburg, Germany

CORRESPONDENCE Hiroshi Takayanagi: taka.csi{at}tmd.ac.jp

NFATc1 and NFATc2 are functionally redundant in the immune system, but it was suggested that NFATc1 is required exclusively for differentiation of osteoclasts in the skeletal system. Here we provide genetic evidence that NFATc1 is essential for osteoclast differentiation in vivo by adoptive transfer of NFATc1^–/– hematopoietic stem cells to osteoclast-deficient Fos^–/– mice, and by Fos^–/– blastocyst complementation, thus avoiding the embryonic lethality of NFATc1^–/– mice. However, in vitro osteoclastogenesis in NFATc1-deficient cells was rescued by ectopic expression of NFATc2. The discrepancy between the in vivo essential role of NFATc1 and the in vitro effect of NFATc2 was attributed to selective autoregulation of the NFATc1 gene by NFAT through its promoter region. This suggested that an epigenetic mechanism contributes to the essential function of NFATc1 in cell lineage commitment. Thus, this study establishes that NFATc1 represents a potential therapeutic target for bone disease and reveals a mechanism that underlies the essential role of NFATc1 in bone homeostasis.

Abbreviations used: AP, activator protein; BMM, bone marrow monocyte/macrophage precursor cell; CBP, CREB-binding protein; ChIP, chromatin immunoprecipitation; ES, embryonic stem; FLC, fetal liver cell; MeCP2, methyl-CpG binding protein 2; RANKL, receptor activator of NF-B ligand.

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