# Glucocorticoid-induced Atrophy in Bone and Muscle

> **NIH NIH R01** · UNIV OF ARKANSAS FOR MED SCIS · 2020 · $225,921

## Abstract

Excess of glucocorticoids (GC) has devastating effects on the musculoskeletal system with 30-50% of long-term
treated patients exhibiting bone fractures. GC induce bone loss by increasing resorption and decreasing for-
mation; and also induce muscle loss and weakness leading to higher incidence of falls. The combined effects on
bone and muscle largely account for the increased fracture risk with GC. Inhibition of resorption (the current
standard of care) stops bone loss; but, markedly reduces bone turnover resulting in microdamage accumulation
with potential development of osteonecrosis of the jaw and atypical fractures; and does not prevent muscle
weakness. Therefore, osteoanabolic therapeutic approaches that build new bone and simultaneously interfere
with GC actions in muscle are sorely needed. Work leading to this application demonstrates that GC increase
the expression of the proteasomal degradation inducers E3 ubiquitin ligases atrogin1, MuRF1, and MUSA1
(atrogenes) in both muscle and bone, a novel finding as atrogenes are traditionally considered muscle-specific.
In addition, inhibition of proteasomal degradation with bortezomib prevents GC-induced osteoblast apoptosis
and, further, bortezomib or silencing of MuRF1 in osteoblasts prevents GC-induced decrease in matrix mineral-
ization in vitro. Moreover, activation of the Vitamin D receptor (VDR) has beneficial musculoskeletal effects and
might prevent falls. We found that VDR signaling prevents GC-induced: 1) atrogene expression in bone and
muscle ex vivo, 2) the increase in Sost expression ex vivo, and 3) apoptosis of osteoblasts and osteocytes in
vitro. Based on these lines of evidence, we hypothesize that atrogene upregulation is a common mechanism
underlying GC actions in bone and muscle and that interventions that interfere with atrogene expression or
function will prevent GC harmful actions in both tissues. We will test this hypothesis using in vivo, ex vivo, and
in vitro approaches. Aim1 will examine whether genetic loss of expression or function of MuRF1 or pharmaco-
logic inhibition of the proteasome with bortezomib interfere with atrogene expression/function and counteracts
GC-induced bone or muscle atrophy in vivo, in prevention and restoration models; and whether genetic deletion
of Notch or FoxO1, or pharmacologic inhibition of Notch signaling prevents muscle atrophy induced by GC. Aim2
will investigate the mechanism of action of VDR signaling on GC-induced bone and muscle atrophy, by examin-
ing whether VDR signaling (induced with 1,25-D3 or eldecalcitol/ED-17, a VDR ligand with reduced hypercalce-
mic action) counteracts GC regulation of proteostasis, mitochondrial dynamics and cellular energetics in bone
and muscle; by studying whether VDR signaling reverses the inhibition of anabolic signaling and the stimulation
of catabolic signaling mediated by Sost upregulation induced by GC in bone, in mice with genetic deletion of the
VDR in muscle (HSA-MerCreMer) and respective con...

## Key facts

- **NIH application ID:** 10225876
- **Project number:** 7R01AR059357-09
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Teresita M. Bellido
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $225,921
- **Award type:** 7
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225876

## Citation

> US National Institutes of Health, RePORTER application 10225876, Glucocorticoid-induced Atrophy in Bone and Muscle (7R01AR059357-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10225876. Licensed CC0.

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