# Negative Regulation of Osteoclastogenesis

> **NIH NIH R01** · HOSPITAL FOR SPECIAL SURGERY · 2020 · $418,000

## Abstract

Myeloid lineage osteoclasts are the sole effective bone-resorbing cells. Many pathological conditions
associated with excessive bone resorption and bone loss are characterized by excessive
osteoclastogenesis. The long term goals of this project are to elucidate new molecular pathways and
mechanisms that suppress osteoclastogenesis, with the associated goal of using this information to develop
new therapeutic approaches to suppress pathological bone resorption.
 Inflammation is an important driver of pathological bone loss. Inflammation decreases bone mass by
suppressing osteoblast-mediated bone formation, and concomitantly strongly promoting bone resorption by
increasing the differentiation and bone-resorbing function of osteoclasts. Thus, inflammation induces local
bone erosion/osteolysis at inflammatory sites in diseases such as rheumatoid arthritis (RA), periodontitis,
infections, and orthopedic peri-implant loosening. Inflammatory sites are also characterized by hypoxia,
which potentiates RANKL-induced osteoclastogenesis by mostly unknown mechanisms. Pathological bone
loss in an inflammatory/hypoxic environment such as RA synovium is resistant to standard anti-resorptive
therapies, and development of new treatments represents an important unmet medical need.
 Based on our overarching hypothesis that augmenting inhibitory mechanisms represents an
attractive alternative therapeutic approach to suppress pathologic bone resorption, in the previous project
period we investigated mechanisms that suppress metabolic and epigenetic pathways important for
osteoclastogenesis and are relevant for inflammatory bone loss. We found that IFN-, well established to
restrain bone loss at inflammatory sites, remodeled the epigenome of human osteoclast precursors,
resulting in remodeling of chromatin and histone marks at enhancers and promoters of key osteoclast
genes. We discovered a new cell-intrinsic negative regulator of osteoclasts, COMMD1, which works by
suppressing NF-B signaling and the induction of anabolic metabolic pathways important for
osteoclastogenesis. Allelic variants that increase COMMD1 expression are associated with decreased bone
loss in RA patients, and myeloid deletion of Commd1 resulted in increased bone loss in inflammatory
models. COMMD1 is inactivated by hypoxia, suggesting that abrogation of this inhibitory mechanism at
hypoxic sites such as RA synovium contributes to pathological bone loss. The extrinsic and intrinsic
negative regulators, IFN- and COMMD1 respectively, converged to suppress the expression and function
of transcription factors important for induction of osteoclast metabolic genes and pathways. These results
identify new inhibitory mechanisms, which we will characterize to obtain knowledge that can be used to
develop new approaches to suppress osteoclastogenesis and pathologic bone resorption by augmenting
these inhibitory mechanisms therapeutically.

## Key facts

- **NIH application ID:** 9880432
- **Project number:** 5R01DE019420-12
- **Recipient organization:** HOSPITAL FOR SPECIAL SURGERY
- **Principal Investigator:** Lionel B Ivashkiv
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,000
- **Award type:** 5
- **Project period:** 2008-09-08 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880432

## Citation

> US National Institutes of Health, RePORTER application 9880432, Negative Regulation of Osteoclastogenesis (5R01DE019420-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9880432. Licensed CC0.

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