Transcriptional modulator Ifrd1 regulates osteoclast differentiation through enhancing the NF-κB/NFATc1 pathway

Takashi Iezaki, Kazuya Fukasawa, Gyujin Park, Tetsuhiro Horie, Takashi Kanayama, Kakeru Ozaki, Yuki Onishi, Yoshifumi Takahata, Yukari Kyumoto, Takeshi Takarada, Yukio Yoneda, Takashi Nakamura, Jean Vacher, Eiichi Hinoi

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Bone homeostasis is maintained by the synergistic actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here, we show that the transcriptional coactivator/repressor interferon-related developmental regulator 1 (Ifrd1) is expressed in osteoclast lineages and represents a component of the machinery that regulates bone homeostasis. Ifrd1 expression was transcriptionally regulated in preosteoclasts by receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) through activator protein 1. Global deletion of murine Ifrd1 increased bone formation and decreased bone resorption, leading to a higher bone mass. Deletion of Ifrd1 in osteoclast precursors prevented RANKL-induced bone loss, although no bone loss was observed under normal physiological conditions. RANKL-dependent osteoclastogenesis was impaired in vitro in Ifrd1-deleted bone marrow macrophages (BMMs). Ifrd1 deficiency increased the acetylation of p65 at residues K122 and K123 via the inhibition of histone deacetylase- dependent deacetylation in BMMs. This repressed the NF-κB-dependent transcription of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), an essential regulator of osteoclastogenesis. These findings suggest that an Ifrd1/NF-κB/NFATc1 axis plays a pivotal role in bone remodeling in vivo and represents a therapeutic target for bone diseases.

Original languageEnglish
Pages (from-to)2451-2463
Number of pages13
JournalMolecular and cellular biology
Volume36
Issue number19
DOIs
Publication statusPublished - Jan 1 2016

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NFATC Transcription Factors
Osteoclasts
Interferons
Bone and Bones
Osteogenesis
Homeostasis
Bone Marrow
Macrophages
Histone Deacetylases
Bone Remodeling
Bone Diseases
Transcription Factor AP-1
Acetylation
Bone Resorption
Cytoplasmic and Nuclear Receptors
3'-(1-butylphosphoryl)adenosine
Osteoblasts
Transcription Factors
Ligands

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Transcriptional modulator Ifrd1 regulates osteoclast differentiation through enhancing the NF-κB/NFATc1 pathway. / Iezaki, Takashi; Fukasawa, Kazuya; Park, Gyujin; Horie, Tetsuhiro; Kanayama, Takashi; Ozaki, Kakeru; Onishi, Yuki; Takahata, Yoshifumi; Kyumoto, Yukari; Takarada, Takeshi; Yoneda, Yukio; Nakamura, Takashi; Vacher, Jean; Hinoi, Eiichi.

In: Molecular and cellular biology, Vol. 36, No. 19, 01.01.2016, p. 2451-2463.

Research output: Contribution to journalArticle

Iezaki, T, Fukasawa, K, Park, G, Horie, T, Kanayama, T, Ozaki, K, Onishi, Y, Takahata, Y, Kyumoto, Y, Takarada, T, Yoneda, Y, Nakamura, T, Vacher, J & Hinoi, E 2016, 'Transcriptional modulator Ifrd1 regulates osteoclast differentiation through enhancing the NF-κB/NFATc1 pathway', Molecular and cellular biology, vol. 36, no. 19, pp. 2451-2463. https://doi.org/10.1128/MCB.01075-15
Iezaki, Takashi ; Fukasawa, Kazuya ; Park, Gyujin ; Horie, Tetsuhiro ; Kanayama, Takashi ; Ozaki, Kakeru ; Onishi, Yuki ; Takahata, Yoshifumi ; Kyumoto, Yukari ; Takarada, Takeshi ; Yoneda, Yukio ; Nakamura, Takashi ; Vacher, Jean ; Hinoi, Eiichi. / Transcriptional modulator Ifrd1 regulates osteoclast differentiation through enhancing the NF-κB/NFATc1 pathway. In: Molecular and cellular biology. 2016 ; Vol. 36, No. 19. pp. 2451-2463.
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