title: Genomewide comprehensive analysis reveals critical cooperation between Smad and c-Fos in RANKL-induced osteoclastogenesis.
abstract: We have previously reported that transforming growth factor β (TGF-β) plays an essential role in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. However, the detailed underlying molecular mechanisms still remain unclear. Formaldehyde-assisted isolation of regulatory elements (FAIRE) and chromatin immunoprecipitation (ChIP) followed by sequencing (FAIRE-seq and ChIP-seq) analyses indicated the cooperation of Smad2/3 with c-Fos during osteoclastogenesis. Biochemical analysis and immunocytochemical analysis revealed that physical interaction between Smad2/3 and c-Fos is required for their nuclear translocation. The gene expression of nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1), a key regulator of osteoclastogenesis, was regulated by RANKL and TGF-β, and c-Fos binding to open chromatin sites was suppressed by inhibition of TGF-β signaling by SB431542. Conversely, Smad2/3 binding to Nfatc1 was impaired by c-Fos deficiency. These results suggest that TGF-β regulates RANKL-induced osteoclastogenesis through reciprocal cooperation between Smad2/3 and c-Fos.
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Omata
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yasui
authors.forename: Jun
authors.initials: J
authors.lastname: Hirose
authors.forename: Naohiro
authors.initials: N
authors.lastname: Izawa
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Imai
authors.forename: Takumi
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Hironari
authors.initials: H
authors.lastname: Masuda
authors.forename: Naoto
authors.initials: N
authors.lastname: Tokuyama
authors.forename: Shinya
authors.initials: S
authors.lastname: Nakamura
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yasuda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Okamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Hikita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
authors.forename: Taku
authors.initials: T
authors.lastname: Saito
authors.forename: Yuho
authors.initials: Y
authors.lastname: Kadono
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Sakae
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D002843:Chromatin / Q000378:metabolism; D016678:Genome; D006801:Humans; D008297:Male; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D053245:RANK Ligand / Q000494:pharmacology*; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta
chemical_list: D002843:Chromatin; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D051785:Smad Proteins; D016212:Transforming Growth Factor beta
keywords: CELL/TISSUE SIGNALING; CYTOKINES; MOLECULAR PATHWAYS; OSTEOCLAST; TRANSCRIPTION FACTORS