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

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

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. © 2019 American Society for Bone and Mineral Research.

Keywords: DENTAL BIOLOGY; EPIGENETICS; OSTEOCLASTS; OSTEOIMMUNOLOGY; OSTEOPOROSIS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged, 80 and over
  • Animals
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Interferon Regulatory Factors / chemistry
  • Interferon Regulatory Factors / deficiency
  • Interferon Regulatory Factors / genetics*
  • Interferon-gamma / pharmacology
  • Jaw / pathology
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Middle Aged
  • Mutation / genetics*
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism*
  • Osteogenesis / drug effects
  • Osteogenesis / genetics
  • Pedigree
  • Root Resorption / genetics*
  • Root Resorption / pathology
  • Signal Transduction / drug effects
  • Transcription, Genetic* / drug effects
  • Transcriptome / genetics

Substances

  • Interferon Regulatory Factors
  • Lipopolysaccharides
  • interferon regulatory factor-8
  • Interferon-gamma