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.
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7 November 2005
Article|
November 07 2005
Autoamplification of NFATc1 expression determines its essential role in bone homeostasis
Masataka Asagiri,
Masataka Asagiri
1Department of Cell Signaling, Graduate School
4Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
5Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
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Kojiro Sato,
Kojiro Sato
1Department of Cell Signaling, Graduate School
4Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
5Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
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Takako Usami,
Takako Usami
7Laboratory of Recombinant Animals, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
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Sae Ochi,
Sae Ochi
1Department of Cell Signaling, Graduate School
2Department of Medicine and Rheumatology, Graduate School
4Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
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Hiroshi Nishina,
Hiroshi Nishina
8Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
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Hiroki Yoshida,
Hiroki Yoshida
6Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
9Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga City, Saga 849-8501, Japan
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Ikuo Morita,
Ikuo Morita
3Department of Cellular Physiological Chemistry, Graduate School
4Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
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Erwin F. Wagner,
Erwin F. Wagner
10Research Institute of Molecular Pathology, A-1030 Vienna, Austria
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Tak W. Mak,
Tak W. Mak
11Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada
12Department of Medical Biophysics, Advanced Medical Discovery Institute, University of Toronto, Toronto, Ontario M5G 2C1, Canada
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Edgar Serfling,
Edgar Serfling
13Department of Molecular Pathology, Institute of Pathology, University of Wüerzburg, D-97080 Wüerzburg, Germany
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Hiroshi Takayanagi
Hiroshi Takayanagi
1Department of Cell Signaling, Graduate School
4Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
5Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
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Masataka Asagiri
1Department of Cell Signaling, Graduate School
4Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
5Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
Kojiro Sato
1Department of Cell Signaling, Graduate School
4Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
5Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
Takako Usami
7Laboratory of Recombinant Animals, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
Sae Ochi
1Department of Cell Signaling, Graduate School
2Department of Medicine and Rheumatology, Graduate School
4Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
Hiroshi Nishina
8Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
Hiroki Yoshida
6Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
9Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga City, Saga 849-8501, Japan
Ikuo Morita
3Department of Cellular Physiological Chemistry, Graduate School
4Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
Erwin F. Wagner
10Research Institute of Molecular Pathology, A-1030 Vienna, Austria
Tak W. Mak
11Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada
12Department of Medical Biophysics, Advanced Medical Discovery Institute, University of Toronto, Toronto, Ontario M5G 2C1, Canada
Edgar Serfling
13Department of Molecular Pathology, Institute of Pathology, University of Wüerzburg, D-97080 Wüerzburg, Germany
Hiroshi Takayanagi
1Department of Cell Signaling, Graduate School
4Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
5Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
CORRESPONDENCE Hiroshi Takayanagi: [email protected]
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-κB ligand.
Received:
June 07 2005
Accepted:
September 13 2005
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2005
J Exp Med (2005) 202 (9): 1261–1269.
Article history
Received:
June 07 2005
Accepted:
September 13 2005
Citation
Masataka Asagiri, Kojiro Sato, Takako Usami, Sae Ochi, Hiroshi Nishina, Hiroki Yoshida, Ikuo Morita, Erwin F. Wagner, Tak W. Mak, Edgar Serfling, Hiroshi Takayanagi; Autoamplification of NFATc1 expression determines its essential role in bone homeostasis . J Exp Med 7 November 2005; 202 (9): 1261–1269. doi: https://doi.org/10.1084/jem.20051150
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