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PMID: 16275763 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Autoamplification of NFATc1 expression determines its essential role in bone homeostasis.

The Journal of experimental medicine ·Vol. 202 ·No. 9 ·2005-11-07 ·Pages 1261-9

Asagiri M, Sato K, Usami T, Ochi S, Nishina H, Yoshida H, Morita I, Wagner EF, Mak TW, Serfling E, Takayanagi H

Abstract

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.

MeSH Terms
Animals Blastocyst/physiology Bone and Bones/physiology Cell Differentiation/genetics Cells, Cultured Epigenesis, Genetic/physiology Fetal Tissue Transplantation/immunology Homeostasis/genetics Liver/cytology Mice Mice, Knockout NFATC Transcription Factors/biosynthesis,deficiency,genetics,physiology Osteoclasts/cytology,physiology Promoter Regions, Genetic Proto-Oncogene Proteins c-fos/deficiency,genetics
Chemicals
NFATC Transcription Factors Nfatc1 protein, mouse Nfatc2 protein, mouse Proto-Oncogene Proteins c-fos
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Asagiri Masataka
Department of Cell Signaling, Tokyo Medical and Dental University, Japan.
Sato Kojiro
Usami Takako
Ochi Sae
Nishina Hiroshi
Yoshida Hiroki
Morita Ikuo
Wagner Erwin F
Mak Tak W
Serfling Edgar
Takayanagi Hiroshi
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34 references, click to expand
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20051150
Published
2005-11-07
Pages
1261-9
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2213228
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20051150 PMC Full Text View journal details
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