Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway

• Published in: Molecular and cellular biology Vol. 36; no. 19; pp. 2451 - 2463
• Main Authors: Iezaki, Takashi, Fukasawa, Kazuya, Park, Gyujin, Horie, Tetsuhiro, Kanayama, Takashi, Ozaki, Kakeru, Onishi, Yuki, Takahata, Yoshifumi, Nakamura, Yukari, Takarada, Takeshi, Yoneda, Yukio, Nakamura, Takashi, Vacher, Jean, Hinoi, Eiichi
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.10.2016; American Society for Microbiology
• Subjects: acetylation; Animals; bone density; bone formation; bone marrow; bone resorption; Cell Differentiation - drug effects; Cells, Cultured; Gene Deletion; Gene Expression Regulation - drug effects; histones; homeostasis; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; ligands; macrophages; Macrophages - cytology; Macrophages - drug effects; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; NF-kappa B - metabolism; NFATC Transcription Factors - metabolism; osteoblasts; osteoclasts; Osteoclasts - cytology; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteogenesis - drug effects; RANK Ligand - pharmacology; Signal Transduction - drug effects; therapeutics; transcription (genetics); Transcription Factor AP-1 - metabolism; transcription factors; Up-Regulation
• ISSN: 1098-5549; 0270-7306; 1098-5549
• DOI: 10.1128/MCB.01075-15

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.