Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption: IRF8 MUTATION AND OSTEOCLAST-MEDIATED TOOTH ROOT RESORPTION

This is the first study 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 to 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 to Irf8+/+ controls. Genome-wide 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.