# Molecular mechanisms of glucocorticoid-induced bone loss

> **NIH VA I01** · CENTRAL ARKANSAS VETERANS HLTHCARE SYS · 2020 · —

## Abstract

Glucocorticoid administration is frequently used to suppress inflammation and treat a variety of conditions in the
VA patient population. One of the most significant side effects of this therapy is bone loss and increased risk of
fracture. We have developed a murine model of glucocorticoid-induced bone loss that mimics many of the
structural and histological changes observed in humans. In addition, we have used mice with genetic deletion
of the glucocorticoid receptor in specific cell types to identify the targets of glucocorticoid action on the skeleton.
We found that deletion of the glucocorticoid receptor from osteoblast lineage cells prevents the stimulation of
bone resorption and the suppression of bone formation caused by glucocorticoid administration. However, the
molecular mechanisms by which glucocorticoids stimulate bone resorption and suppress bone formation by
acting on this cell type remain unclear. Based on preliminary studies, we propose the central hypothesis that
glucocorticoids stimulate bone resorption by suppressing expression of osteoprotegerin (OPG) and that they
suppress bone formation by antagonizing canonical Wnt signaling. To address this hypothesis we will identify
the molecular mechanisms by which glucocorticoids suppress expression of the OPG gene using a combination
of large transcriptional reporter constructs and deletion of regulatory sequences from the endogenous OPG gene
in cells and mice (Aim 1). We will also determine whether glucocorticoids suppress bone formation by stimulating
the apoptosis of osteoblast lineage cells by blocking induction of apoptosis in this cell type. This will be
accomplished by deletion of genes essential for apoptosis (Bak, Bax, and Caspase 8) in this cell lineage (Aim
2). Lastly, we will determine whether glucocorticoids suppress bone formation by opposing Wnt signaling by
creating mice with constitutive activation of β-catenin in osteoblasts and treating them with exogenous
glucocorticoids. If our hypothesis is correct, this maneuver will prevent suppression of bone formation by
glucocorticoids (Aim 3). Overall, the proposed studies will clarify the molecular changes by which glucocorticoid
excess causes bone loss and may identify novel approaches to prevent this bone loss in patients that require
chronic glucocorticoid therapy.

## Key facts

- **NIH application ID:** 9829488
- **Project number:** 5I01BX000294-10
- **Recipient organization:** CENTRAL ARKANSAS VETERANS HLTHCARE SYS
- **Principal Investigator:** CHARLES A O'BRIEN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9829488

## Citation

> US National Institutes of Health, RePORTER application 9829488, Molecular mechanisms of glucocorticoid-induced bone loss (5I01BX000294-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9829488. Licensed CC0.

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