title: The Transcriptional Modulator Interferon-Related Developmental Regulator 1 in Osteoblasts Suppresses Bone Formation and Promotes Bone Resorption.
abstract: Bone homeostasis is maintained by the synergistic actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Although interferon-related developmental regulator 1 (Ifrd1) has been identified as a transcriptional coactivator/repressor in various cells, little attention has been paid to its role in osteoblastogenesis and bone homeostasis thus far. Here, we show that Ifrd1 is a critical mediator of both the cell-autonomous regulation of osteoblastogenesis and osteoblast-dependent regulation of osteoclastogenesis. Osteoblast-specific deletion of murine Ifrd1 increased bone formation and decreased bone resorption, causing high bone mass. Ifrd1 deficiency enhanced osteoblast differentiation and maturation along with increased expression of Runx2 and osterix (Osx). Mechanistically, Ifrd1 deficiency increased the acetylation status of p65, a component of NF-κB, at residues K122 and K123 via the attenuation of the interaction between p65 and histone deacetylase (HDAC). This led to the nuclear export of p65 and a decrease in NF-κB-dependent Smad7 expression and the subsequent enhancement of Smad1/Smad5/Smad8-dependent transcription. Moreover, a high bone mass phenotype in the osteoblast-specific deletion of Ifrd1 was markedly rescued by the introduction of one Osx-floxed allele but not of Runx2-floxed allele. Coculture experiments revealed that Ifrd1-deficient osteoblasts have a higher osteoprotegerin (OPG) expression and a lower ability to support osteoclastogenesis. Ifrd1 deficiency attenuated the interaction between β-catenin and HDAC, subsequently increasing the acetylation of β-catenin at K49, leading to its nuclear accumulation and the activation of the β-catenin-dependent transcription of OPG. Collectively, the expression of Ifrd1 in osteoblasts repressed osteoblastogenesis and activated osteoclastogenesis through modulating the NF-κB/Smad/Osx and β-catenin/OPG pathways, respectively. These findings suggest that Ifrd1 has a pivotal role in bone homeostasis through its expression in osteoblasts 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: 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: 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: 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: 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: Koichi
authors.initials: K
authors.lastname: Fujikawa
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: Animal Resource Development Unit, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies (CLST), Kobe, Hyogo, Japan.|Genetic Engineering Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies (CLST), Kobe, Hyogo, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Genetic Engineering Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies (CLST), Kobe, Hyogo, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Shioi
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hinoi
mesh_terms: D000107:Acetylation; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology*; D001842:Bone and Bones / Q000473:pathology; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D017353:Gene Deletion; D006655:Histone Deacetylases / Q000378:metabolism; D006706:Homeostasis; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis; D053244:Osteoprotegerin / Q000378:metabolism; D010641:Phenotype; D051785:Smad Proteins / Q000378:metabolism; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C490044:Ifrd1 protein, mouse; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D053244:Osteoprotegerin; C493716:Runx2 protein, mouse; D051785:Smad Proteins; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D051176:beta Catenin; D006655:Histone Deacetylases
keywords: HDAC; NF-κB; OSTEOBLASTS; OSTERIX; WNT/β-CATENIN