| First Author | Thumbigere-Math V | Year | 2019 |
| Journal | J Bone Miner Res | Volume | 34 |
| Issue | 6 | Pages | 1155-1168 |
| PubMed ID | 30840779 | Mgi Jnum | J:277621 |
| Mgi Id | MGI:6342304 | Doi | 10.1002/jbmr.3690 |
| Citation | Thumbigere-Math V, et al. (2019) Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption. J Bone Miner Res 34(6):1155-1168 |
| abstractText | This is the first study to our knowledge to report a novel mutation in the interferon regulatory factor 8 gene (IRF8(G388S) ) associated with multiple idiopathic tooth root resorption, a form of periodontal disease. The IRF8(G388S) variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. Functional assays demonstrated that the IRF8(G388S) mutant promoted osteoclastogenesis and failed to inhibit NFATc1-dependent transcriptional activation when compared with IRF8(WT) control. Further, similar to subjects with heterozygous IRF8(G388S) 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. (c) 2019 American Society for Bone and Mineral Research. |
