Identification of Nedd9 as a TGF-β-Smad2/3 target gene involved in RANKL-Induced osteoclastogenesis by comprehensive analysis

Yasunori Omata, Shinya Nakamura, Takuma Koyama, Tetsuro Yasui, Jun Hirose, Naohiro Izawa, Takumi Matsumoto, Yuuki Imai, Sachiko Seo, Mineo Kurokawa, Shuichi Tsutsumi, Yuho Kadono, Chikao Morimoto, Hiroyuki Aburatani, Takeshi Miyamoto, Sakae Tanaka

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Abstract

TGF-ß is a multifunctional cytokine that is involved in cell proliferation, differentiation and function. We previously reported an essential role of the TGF-ß -Smad2/3 pathways in RANKL-induced osteoclastogenesis. Using chromatin immunoprecipitation followed by sequencing, we comprehensively identified Smad2/3 target genes in bone marrow macrophages. These genes were enriched in the gene population upregulated by TGF-ß and downregulated by RANKL. Recent studies have revealed that histone modifications, such as trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3), critically regulate key developmental steps. We identified Nedd9 as a Smad2/3 target gene whose histone modification pattern was converted from H3K4me3(+)/H3K4me27(+) to H3K4me3 (+)/H3K4me27(-) by TGF-ß. Nedd9 expression was increased by TGF-ß and suppressed by RANKL. Overexpression of Nedd9 partially rescued an inhibitory effect of a TGF-ß inhibitor, while gene silencing of Nedd9 suppressed RANKL-induced osteoclastogenesis. RANKL-induced osteoclastogenesis were reduced and stimulatory effects of TGF-ß on RANKL-induced osteoclastogenesis were partially abrogated in cells from Nedd9-deficient mice although knockout mice did not show abnormal skeletal phenotypes. These results suggest that Nedd9 is a Smad2/3 target gene implicated in RANKL-induced osteoclastogenesis.

Original languageEnglish
Article numbere0157992
JournalPLoS One
Volume11
Issue number6
DOIs
Publication statusPublished - 2016 Jun 1

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Omata, Y., Nakamura, S., Koyama, T., Yasui, T., Hirose, J., Izawa, N., Matsumoto, T., Imai, Y., Seo, S., Kurokawa, M., Tsutsumi, S., Kadono, Y., Morimoto, C., Aburatani, H., Miyamoto, T., & Tanaka, S. (2016). Identification of Nedd9 as a TGF-β-Smad2/3 target gene involved in RANKL-Induced osteoclastogenesis by comprehensive analysis. PLoS One, 11(6), [e0157992]. https://doi.org/10.1371/journal.pone.0157992