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

Hiroshi Takayanagi; Sunhwa Kim; Takako Koga; Hiroshi Nishina; Masashi Isshiki; Hiroki Yoshida; Akio Saiura; Miho Isobe; Taeko Yokochi; Jun-ichiro Inoue; Erwin F Wagner; Tak W Mak; Tatsuhiko Kodama; Tadatsugu Taniguchi

doi:10.1016/s1534-5807(02)00369-6

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

Dev Cell. 2002 Dec;3(6):889-901. doi: 10.1016/s1534-5807(02)00369-6.

Authors

Hiroshi Takayanagi¹, Sunhwa Kim, Takako Koga, Hiroshi Nishina, Masashi Isshiki, Hiroki Yoshida, Akio Saiura, Miho Isobe, Taeko Yokochi, Jun-ichiro Inoue, Erwin F Wagner, Tak W Mak, Tatsuhiko Kodama, Tadatsugu Taniguchi

Affiliation

¹ Department of Immunology, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Japan.

PMID: 12479813
DOI: 10.1016/s1534-5807(02)00369-6

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 Ca(2+) 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus / drug effects
Active Transport, Cell Nucleus / genetics
Animals
Calcineurin / genetics
Calcineurin / metabolism
Calcium Signaling / drug effects
Calcium Signaling / genetics
Carrier Proteins / genetics*
Carrier Proteins / metabolism
Carrier Proteins / pharmacology
Cell Culture Techniques
Cell Differentiation / drug effects
Cell Differentiation / genetics*
Cells, Cultured
DNA-Binding Proteins / deficiency*
DNA-Binding Proteins / genetics
Gene Expression Regulation / drug effects
Gene Expression Regulation / genetics
Genetic Testing
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / drug effects
Hematopoietic Stem Cells / metabolism*
Membrane Glycoproteins / genetics*
Membrane Glycoproteins / metabolism
Membrane Glycoproteins / pharmacology
Mice
Mice, Inbred C57BL
NFATC Transcription Factors
Nuclear Proteins*
Oligonucleotide Array Sequence Analysis
Osteoclasts / cytology
Osteoclasts / drug effects
Osteoclasts / metabolism*
Promoter Regions, Genetic / drug effects
Promoter Regions, Genetic / genetics
Proteins / genetics
Proteins / metabolism
Proto-Oncogene Proteins c-fos / genetics
Proto-Oncogene Proteins c-fos / metabolism
RANK Ligand
RNA, Messenger / metabolism
Receptor Activator of Nuclear Factor-kappa B
Signal Transduction / drug effects
Signal Transduction / genetics*
TNF Receptor-Associated Factor 6
Transcription Factors / deficiency*
Transcription Factors / genetics
Transcription, Genetic / drug effects
Transcription, Genetic / genetics

Substances

Carrier Proteins
DNA-Binding Proteins
Membrane Glycoproteins
NFATC Transcription Factors
Nfatc1 protein, mouse
Nuclear Proteins
Proteins
Proto-Oncogene Proteins c-fos
RANK Ligand
RNA, Messenger
Receptor Activator of Nuclear Factor-kappa B
TNF Receptor-Associated Factor 6
Tnfrsf11a protein, mouse
Tnfsf11 protein, mouse
Transcription Factors
Calcineurin