Genomewide comprehensive analysis reveals critical cooperation between smad and c-Fos in RANKL-induced osteoclastogenesis

Yasunori Omata, Tetsuro Yasui, Jun Hirose, Naohiro Izawa, Yuuki Imai, Takumi Matsumoto, Hironari Masuda, Naoto Tokuyama, Shinya Nakamura, Shuichi Tsutsumi, Hisataka Yasuda, Kazuo Okamoto, Hiroshi Takayanagi, Atsuhiko Hikita, Takeshi Imamura, Koichi Matsuo, Taku Saito, Yuho Kadono, Hiroyuki Aburatani, Sakae Tanaka

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24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)869-877
Number of pages9
JournalJournal of Bone and Mineral Research
Volume30
Issue number5
DOIs
Publication statusPublished - 2015 May 1

Keywords

  • Cell/tissue signaling
  • Cytokines
  • Molecular pathways
  • Osteoclast
  • Transcription factors

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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    Omata, Y., Yasui, T., Hirose, J., Izawa, N., Imai, Y., Matsumoto, T., Masuda, H., Tokuyama, N., Nakamura, S., Tsutsumi, S., Yasuda, H., Okamoto, K., Takayanagi, H., Hikita, A., Imamura, T., Matsuo, K., Saito, T., Kadono, Y., Aburatani, H., & Tanaka, S. (2015). Genomewide comprehensive analysis reveals critical cooperation between smad and c-Fos in RANKL-induced osteoclastogenesis. Journal of Bone and Mineral Research, 30(5), 869-877. https://doi.org/10.1002/jbmr.2418