Mouse Homolog of Human IRF8G388SMutation Provides Novel Insight into Osteoclastogenesis and Tooth Root Resorption

Author:

Das Amitabh,Yesupatham Sathish Kumar,Allison Devon,Tanwar Himanshi,Gnanasekaran JebaMercy,Kear Bernice,Wang Xiaobei,Wang Sheng,Zachariadou Christina,Abbasi Yasaman,Chung Man-Kyo,Ozato Keiko,Liu Chengyu,Foster Brian L.,Thumbigere-Math Vivek

Abstract

ABSTRACTPreviously, we reported a novel mutation in the Interferon Regulatory Factor 8 (IRF8) gene associated with multiple idiopathic cervical root resorption (MICRR), an aggressive form of tooth root resorption mediated by increased osteoclast activity. The IRF8 G388S variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. To investigate the molecular basis of MICRR and IRF8 function, we generatedIrf8knock-in (KI) mice using CRISPR/Cas9 modeling the humanIRF8G388Smutation. The heterozygous (Het) and homozygous (Homo)Irf8 KImice showed no gross morphological defects, and the development of hematopoietic cells was unaffected and similar to that in wild-type (WT) mice. TheIrf8 KIHet and Homo mice showed no difference in macrophage gene signatures important for antimicrobial defenses and inflammatory cytokine production. Consistent with the phenotype observed in MICRR patients,Irf8 KIHet and Homo mice demonstrated significantly increased osteoclast formation and resorption activityin vivoandin vitrowhen compared to WT mice. The oral ligature insertedIrf8 KIHet and Homo mice displayed increased osteoclast-mediated alveolar bone loss and tooth root resorption compared to WT mice. The increased osteoclastogenesis noted in KI mice is due to the inability of mutantIrf8G388S isoform to negatively inhibit NFATc1-dependent transcriptional activation and downstream osteoclast specific transcripts. This translational study delineates the IRF8 domain important for osteoclast function and provides novel insights into theIRF8mutation associated with MICRR.Irf8G388Smutation mainly affects osteoclastogenesis while sparing immune cell development and function. TheIrf8 KImice serve as a novel translational model for studying the etiopathology of MICRR and developing targeted therapies for MICRR and other skeletal disorders mediated by increased osteoclast activity.

Publisher

Cold Spring Harbor Laboratory

Reference60 articles.

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