title: Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway.
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.
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Iezaki
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Fukasawa
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Gyujin
authors.initials: G
authors.lastname: Park
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Horie
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanayama
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Kakeru
authors.initials: K
authors.lastname: Ozaki
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Onishi
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Takahata
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takarada
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yoneda
authors.affiliation: Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM), Département de Médecine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Vacher
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan hinoi@p.kanazawa-u.ac.jp.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hinoi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C490044:Ifrd1 protein, mouse; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; D018808:Transcription Factor AP-1