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J Bone Miner Res. 2015 May;30(5):869-77. doi: 10.1002/jbmr.2418.

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

Author information

1
Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

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.

KEYWORDS:

CELL/TISSUE SIGNALING; CYTOKINES; MOLECULAR PATHWAYS; OSTEOCLAST; TRANSCRIPTION FACTORS

PMID:
25431176
DOI:
10.1002/jbmr.2418
[Indexed for MEDLINE]
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