Inactivating Mutation in <i>IRF8</i> Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption

Thumbigere‐Math, Vivek; Foster, Brian L.; Bachu, Mahesh; Yoshii, Hiroaki; Brooks, Stephen R.; Coulter, Alyssa; Chavez, Michael B.; Togi, Sumihito; Neely, Anthony L.; Deng, Zuoming; Mansky, Kim C.; Ozato, Keiko; Somerman, Martha J.

doi:10.1002/jbmr.3690

Cited by 23 publications

(59 citation statements)

References 56 publications

(122 reference statements)

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“…IRF8 deficiency in OC precursors but not osteoblasts is known to promote osteoclastogenesis (Thumbigere-Math et al, 2019;Zhao et al, 2009). Hence, to study the effects of conditional deletion of Irf8 in OC precursors, we analyzed Irf8 cKO mice for abnormal bone and OC phenotypes.…”

Section: Transcriptomic Resultsmentioning

confidence: 99%

“…Previously, IRF8's role in osteoclastogenesis has been studied using Irf8 global knock-out (Irf8 gKO) mice (Izawa et al, 2019;Thumbigere-Math et al, 2019;Zhao et al, 2009). However, the severely altered population and properties of HSCs in Irf8 gKO mice (Holtschke et al, 1996;Tamura and Ozato, 2002), along with the development of chronic myelogenous leukemia and splenomegaly, has limited the genome-wide analysis of IRF8 function in OC precursors derived from a monocyte/macrophage lineage.…”

Section: Generation Of Irf8 Cko Mice and Characterization Of Hscsmentioning

confidence: 99%

“…The following mouse strains were used in this study: Irf8 fl/fl mice (Feng et al, 2011), Csf1r cre mice (Deng et al, 2010), Irf8 gKO mice and Irf8 gWT mice (Tamura and Ozato, 2002;Thumbigere-Math et al, 2019). Irf8 cKO mice were generated by crossing Irf8 fl/fl mice with Csf1r cre mice, a monocyte/macrophage targeting Cre driver mice.…”

Section: Experimental Model and Subject Detailsmentioning

confidence: 99%

“…Osteoclast assays were performed as described previously (Thumbigere-Math et al, 2019). For were directly plated in 24-well plates at 2x10 5 cells/cm 2 or 48-well plates at 1x10 5 cells/cm 2 or 96-well plates at 0.3x10 5 cells/cm 2 and supplemented with 20 ng/ml M-CSF for 2 days, followed by treatment with 40 ng/mL RANKL.…”

Section: In Vitro Osteoclast Assaymentioning

confidence: 99%

“…Furthermore, the role of lineage determining TFs in regulating OC differentiation on a genome-wide scale remains poorly understood. IRF8, apart from playing an important role in myelopoiesis (Hambleton et al, 2011;Kurotaki et al, 2019;Kurotaki et al, 2013;Tamura et al, 2000;Tamura and Ozato, 2002), also functions as a negative regulator of OC by inhibiting NFATc1, a master regulator of osteoclastogenesis (Fang et al, 2016;Thumbigere-Math et al, 2019;Zhao et al, 2009). In this study, we utilized a novel Irf8 conditional knockout (Irf8 cKO) mouse model to characterize the importance of IRF8 in OC progenitor development and epigenetic regulation of OC differentiation.…”

Section: Introductionmentioning

confidence: 99%

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Monocyte Subsets with High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8

Das

Wang

Kang

et al. 2020

Preprint

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Osteoclasts (OCs) are bone resorbing cells formed by the serial fusion of monocytes. In mice and humans, three distinct subsets of monocytes exist; however, it is unclear if all of them exhibit osteoclastogenic potential. Here we show that in wild-type mice, Ly6C hi and Ly6C int monocytes are the primary source of OC formation when compared to Ly6Cmonocytes. Their osteoclastogenic potential is dictated by increased expression of signaling receptors and activation of pre-established transcripts, as well as de novo gain in enhancer activity and promoter changes. In the absence of IRF8, a transcription factor important for myelopoiesis and osteoclastogenesis, all three monocyte subsets are programmed to display higher osteoclastogenic potential. Enhanced NFATc1 nuclear translocation and amplified transcriptomic and epigenetic changes initiated at early developmental stages direct the increased osteoclastogenesis in Irf8 deficient mice. Collectively, our study provides novel insights into the transcription factors and active cis-regulatory elements that regulate OC differentiation.Service for assistance with cell sorting. We thank Satish Yesupatham from University of Maryland School of Dentistry for assistance with FACS. We thank Kim C. Mansky from University of Minnesota for critically reviewing this manuscript. Funding sources: R00DE028439 to V.T.M.; start-up funds from Univ. of Maryland School of Dentistry to V.T.M.;

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Section: Transcriptomic Resultsmentioning

confidence: 99%

Section: Generation Of Irf8 Cko Mice and Characterization Of Hscsmentioning

confidence: 99%

Section: Experimental Model and Subject Detailsmentioning

confidence: 99%

Section: In Vitro Osteoclast Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Monocyte Subsets with High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8

Das

Wang

Kang

et al. 2020

Preprint

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Hepatic interferon regulatory factor 8 expression suppresses hepatocellular carcinoma progression and enhances the response to anti–programmed cell death protein‐1 therapy

Yan

Shi

et al. 2022

Hepatology

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Background and Aims Therapeutic blockade of the programmed cell death protein‐1 (PD‐1) immune checkpoint pathways has resulted in significant reactivation of T cell–mediated antitumor immunity and is a promising clinical anticancer treatment modality in several tumor types, but the durable response rate remains relatively low (15%–20%) in most patients with HCC for unknown reasons. Evidence reveals that the interferon signaling pathway plays a critical role in modulating the efficacy and sensitivity of anti–PD‐1 therapy against multiple tumor types, but the mechanisms are unclear. Approach and Results Using Kaplan‐Meier survival analysis based on HCC databases, we found that deceased expression of interferon regulatory factor (IRF) 8 in HCC, among all the nine IRF members that regulate interferon signals, was associated with poor prognosis of patients with HCC. Moreover, gene set enrichment analysis identified the interferon‐gamma and PD‐1 signaling signatures as the top suppressed pathways in patients with IRF8‐low HCC. Contrarily, overexpression of IRF8 in HCC cells significantly enhanced antitumor effects in immune‐competent mice, modulating infiltration of tumor‐associated macrophages (TAMs) and T cell exhaustion in tumor microenvironment. We further demonstrated that IRF8 regulated recruitment of TAMs by inhibiting the expression of chemokine (C‐C motif) ligand 20 (CCL20). Mechanically, IRF8‐mediated repression of c‐fos transcription resulted in decreased expression of CCL20, rather than directly bound to CCL20 promoter region. Importantly, adeno‐associated virus 8–mediated hepatic IRF8 rescue significantly suppressed HCC progression and enhanced the response to anti–PD‐1 therapy. Conclusions This work identified IRF8 as an important prognostic biomarker in patients with HCC that predicted the response and sensitivity to anti–PD‐1 therapy and uncovered it as a therapeutic target for enhancing the efficacy of immune therapy.

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Monocyte Subsets With High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8

Das

Wang

Kang

et al. 2020

Journal of Bone and Mineral Research

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Osteoclasts (OCs) are bone‐resorbing cells formed by the serial fusion of monocytes. In mice and humans, three distinct subsets of monocytes exist; however, it is unclear if all of them exhibit osteoclastogenic potential. Here we show that in wild‐type (WT) mice, Ly6Chi and Ly6Cint monocytes are the primary source of OC formation when compared to Ly6C− monocytes. Their osteoclastogenic potential is dictated by increased expression of signaling receptors and activation of preestablished transcripts, as well as de novo gain in enhancer activity and promoter changes. In the absence of interferon regulatory factor 8 (IRF8), a transcription factor important for myelopoiesis and osteoclastogenesis, all three monocyte subsets are programmed to display higher osteoclastogenic potential. Enhanced NFATc1 nuclear translocation and amplified transcriptomic and epigenetic changes initiated at early developmental stages direct the increased osteoclastogenesis in Irf8‐deficient mice. Collectively, our study provides novel insights into the transcription factors and active cis‐regulatory elements that regulate OC differentiation. © 2020 American Society for Bone and Mineral Research (ASBMR).

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

Cited by 23 publications

References 56 publications

Monocyte Subsets with High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8

Monocyte Subsets with High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8

Hepatic interferon regulatory factor 8 expression suppresses hepatocellular carcinoma progression and enhances the response to anti–programmed cell death protein‐1 therapy

Monocyte Subsets With High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8

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