# Role of gasdermin D in bone resorption

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $376,101

## Abstract

The study of rare diseases often informs more common pathologies. We have extensively studied the NLRP3
inflammasome, which is mutated in autoinflammatory disorders such as cryopyrin-associated periodic
syndromes (CAPS). A major feature of these conditions is excessive production of IL-1β, which is also highly
induced by procedures such as radiotherapy and chemotherapy, commonly used to kill malignant cells or as a
conditioning regimen for bone marrow transplantation (BMT). IL-1β potently promotes bone resorption while
simultaneously inhibiting bone formation, but IL-1 blocking agents have limited efficacy in the treatment of
syndrome-associated bone pathologies. This suggests that other actions of the inflammasomes beyond IL-1β
processing, contribute to adverse skeletal effects in diseases. The inflammasomes are responsible for the
maturation of IL-1β and IL-18. Recent studies have identified GSDMD as an additional critical substrate of the
inflammasomes. Activated GSDMD translocates to the plasma membrane where it forms pores through which
IL-1β and IL-18 are secreted. However, excessive pore formation compromises membrane integrity, releasing
pro-inflammatory cytoplasmic contents into the extracellular environment. This form of cell death, termed
pyroptosis is inflammatory. Thus, while GSDMD is a normal participant in immune responses and tissue repair,
its chronic activation promotes inflammation. We surmise that the concomitant release of multiple inflammatory
factors during pyroptosis causes pathological bone loss. Therefore, inhibition of GSDMD could provide
superior efficacy over IL-1 blockade, not only in the context of CAPS, but also radiation and chemotherapy.
Recent drug discovery efforts have identified disulfiram as an antagonist of GSDMD-pore forming activity.
Disulfiram is an FDA-approved drug for the treatment of alcohol addiction. We found that administration of
disulfiram to mice inhibited LPS-stimulated IL-1β production. Disulfiram also inhibited IL-1β secretion,
pyroptosis and osteoclast (OC) differentiation in vitro. To further study the role of GSDMD in bone resorption,
we determined skeletal impact of GSDMD loss-of-function in mouse models. Preliminary results indicate that
baseline bone mass was higher in Gsdmd-/- compared to WT mice. Moreover, the exuberant OC formation that
occurred in CAPS mice was normalized upon Gsdmd ablation. Gsdmd null mice were also resistant to
radiation/BMT-induced bone loss. In vitro data further demonstrated that expression of GSDMD was up-
regulated during OC differentiation, and genetic ablation of this protein decreased OC formation. These results
suggest that GSDMD is functional in OC without compromising their survival, and regulates bone resorption.
The central hypothesis of this proposal is that GSDMD regulates bone resorption in pathological conditions
through mechanisms involving its actions in inflammatory cells and OC lineage. We will test this hypothesis in
two Aims: Aim 1: Determ...

## Key facts

- **NIH application ID:** 10335233
- **Project number:** 5R01AR076758-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Gabriel Mbalaviele
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $376,101
- **Award type:** 5
- **Project period:** 2020-02-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10335233

## Citation

> US National Institutes of Health, RePORTER application 10335233, Role of gasdermin D in bone resorption (5R01AR076758-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10335233. Licensed CC0.

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