# Conditional Deletion of Irf8 in Monocyte Macrophage Lineage Provides Novel Insight into Irf8s Important Function in Osteoclast Regulation and Bone Metabolism

> **NIH NIH R03** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $154,500

## Abstract

PROJECT SUMMARY/ABSTRACT
Diseases such as periodontitis, osteoporosis, and rheumatoid arthritis, are characterized by excessive bone
resorption due to increased osteoclast activity. It is estimated that osteoporosis affects ~10 million Americans
with another 19 million at risk. Periodontitis affects ~46% of the U.S. adults aged ³30 years. Rheumatoid arthritis
affects ~54.4 million U.S. adults - equating to about 25% of the population. The impact of these diseases in terms
of social, psychological, and economic burden on individuals, communities, and health services is enormous.
Despite these concerns, the molecular mechanisms contributing to dysregulated osteoclast function in these
pathological conditions remain unclear, creating a critical knowledge gap in developing targeted interventions
and therapeutic strategies. Our long-term goal is to identify and gain an in-depth understanding of the positive
and negative regulators of osteoclast differentiation and utilize the gained knowledge to develop new
interventional and therapeutic approaches for osteoclast-mediated disorders. Towards achieving our long-term
goal, we have identified a novel mutation in the Interferon Regulatory Factor 8 (IRF8) gene that promotes
increased osteoclast activity and susceptibility to a rare periodontal disease termed “Multiple Idiopathic Cervical
Root Resorption (MICRR). The current proposal takes a new direction to gain in-depth knowledge about IRF8
role in osteoclast regulation and periodontal homeostasis. To date, IRF8’s role in osteoclastogenesis has been
studied using Irf8 gKO mice. However, the severely altered population and properties of hematopoietic stem
cells in Irf8 gKO mice has affected the detailed analysis of IRF8 function in osteoclast precursors derived from a
monocyte/macrophage lineage. To overcome this limitation, we have generated a myeloid cell-specific Irf8
conditional knockout (cKO). In this application, we will apply genetic approaches and use both in vitro cell culture
systems and Irf8 cKO mouse model to investigate: 1) Importance of IRF8 in monocyte subset development (2)
Osteoclastogenic potential of different monocyte subsets and how it is influenced by IRF8, and (3) Specific
monocyte subsets contributing to tissue destruction in periodontitis. We will pursue these aims using an
innovative combination of Irf8 cKO mouse model and techniques such next-generation sequencing, flow
cytometry, and micro-CT. The proposed research is significant, because it will provide critical mechanistic
insights into the regulation of complex networks of transcription factors that govern osteoclast differentiation.
This work will develop foundational resources that will be used by other researchers for studying various bone
disorders and inflammatory disorders that have known risk alleles in IRF8. Most importantly, the results will lay
the groundwork to develop better treatment options for various osteoclast-mediated bone disorders, including
periodontal dis...

## Key facts

- **NIH application ID:** 10213697
- **Project number:** 5R03DE029258-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Vivek Thumbigere-Math
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $154,500
- **Award type:** 5
- **Project period:** 2020-07-09 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213697

## Citation

> US National Institutes of Health, RePORTER application 10213697, Conditional Deletion of Irf8 in Monocyte Macrophage Lineage Provides Novel Insight into Irf8s Important Function in Osteoclast Regulation and Bone Metabolism (5R03DE029258-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10213697. Licensed CC0.

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