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J Bone Miner Res. 2019 Jun;34(6):1155-1168. doi: 10.1002/jbmr.3690. Epub 2019 Mar 6.

Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption.

Author information

1
Division of Periodontology, University of Maryland School of Dentistry, Baltimore, MD, USA.
2
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
3
Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, USA.
4
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
5
Division of Graduate Education, Detroit Mercy Dental, Detroit, MI, USA.
6
Department of Developmental and Surgical Sciences, University of Minnesota School of Dentistry, Minneapolis, MN, USA.

Abstract

This is the first study to our knowledge to report a novel mutation in the interferon regulatory factor 8 gene (IRF8G388S ) associated with multiple idiopathic tooth root resorption, a form of periodontal disease. The IRF8G388S variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. Functional assays demonstrated that the IRF8G388S mutant promoted osteoclastogenesis and failed to inhibit NFATc1-dependent transcriptional activation when compared with IRF8WT control. Further, similar to subjects with heterozygous IRF8G388S mutation, Irf8+/- mice exhibited increased osteoclast activity in the mandibular alveolar bone surrounding molar teeth. Immunohistochemistry illustrated increased NFATc1 expression in the dentoalveolar region of Irf8-/- and Irf8+/- mice when compared with Irf8+/+ controls. Genomewide analyses revealed that IRF8 constitutively bound to regulatory regions of several thousand genes in osteoclast precursors, and genetic aberration of IRF8 significantly enhanced many osteoclast-specific transcripts. Collectively, this study delineates the critical role of IRF8 in defining osteoclast lineage and osteoclast transcriptional program, which may help in better understanding of various osteoclast-mediated disorders, including periodontal disease.

KEYWORDS:

DENTAL BIOLOGY; EPIGENETICS; OSTEOCLASTS; OSTEOIMMUNOLOGY; OSTEOPOROSIS

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