Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts.
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.
Takayanagi
Hiroshi
H
Department of Immunology, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Japan.
Kim
Sunhwa
S
Koga
Takako
T
Nishina
Hiroshi
H
Isshiki
Masashi
M
Yoshida
Hiroki
H
Saiura
Akio
A
Isobe
Miho
M
Yokochi
Taeko
T
Inoue
Jun-ichiro
J
Wagner
Erwin F
EF
Mak
Tak W
TW
Kodama
Tatsuhiko
T
Taniguchi
Tadatsugu
T
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005820:Genetic Testing; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand; D012333:RNA, Messenger / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D048029:TNF Receptor-Associated Factor 6; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D009687:Nuclear Proteins; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D048029:TNF Receptor-Associated Factor 6; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D019703:Calcineurin