title: Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts.
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.
authors.affiliation: Department of Immunology, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
authors.forename: Sunhwa
authors.initials: S
authors.lastname: Kim
authors.forename: Takako
authors.initials: T
authors.lastname: Koga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
authors.forename: Masashi
authors.initials: M
authors.lastname: Isshiki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Akio
authors.initials: A
authors.lastname: Saiura
authors.forename: Miho
authors.initials: M
authors.lastname: Isobe
authors.forename: Taeko
authors.initials: T
authors.lastname: Yokochi
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Inoue
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
mesh_terms: 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
chemical_list: 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