# Role of glucocorticoid-suppression of preosteoclast PDGF-BB in skeletal angiogenesis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $360,250

## Abstract

Project Summary
Osteotoxic side effects of glucocorticoids, such as osteoporosis and osteonecrosis, limit clinical use. Children
are a particularly vulnerable population as 30-50% of children on chronic glucocorticoids develop an osteotoxic
side effect and there are no-FDA approved treatments for children. Although there have been extensive studies
about glucocorticoid effects on the bone in the mature skeleton focusing largely on osteoclasts and osteoblasts,
knowledge gaps still exist which in the growing skeleton. Bone, particularly growing bone, is highly vascularized.
A unifying histological feature of osteoporosis, osteonecrosis, and impaired skeletal growth, is reduced bone
vasculature. Glucocorticoids impair skeletal angiogenesis, which correlates with skeletal fragility in animal
models. The purpose of this study is to elucidate the key affected cell and intracellular signaling mechanism
involved in glucocorticoid suppression of angiogenesis and its relation to osteotoxic side effects. We have
established a young glucocorticoid-osteotoxic mouse model. We have found that glucocorticoids drastically
reduce type H vessels, a specific subtype of blood vessels associated with osteogenesis. Building on our prior
work demonstrating that Trap+ preosteoclasts secrete platelet-derived growth factor type BB (PDGF-BB), which
recruits endothelial precursor cells (EPCs) to form type H blood vessels, we found that glucocorticoids suppress
Pdgfb transcription by interfering with binding of nuclear factor kappa beta (NF-κB) to the Pdgfb promoter.
Decreased PDGF-BB was associated with a decreased number of type H vessels, number of mature
osteoblasts, and decreased bone volume. We hypothesize that glucocorticoid suppression of preosteoclast
PDGF-BB via inactivation of NF-κB is the cause of glucocorticoid impairment of skeletal angiogenesis. In this
proposal, we will dissect the key cellular mechanism involved in glucocorticoid suppression of angiogenesis.
Specifically, we will 1) Demonstrate preosteoclasts are the major cell type in glucocorticoid-suppression of
skeletal angiogenesis. 2) Determine the mechanism of glucocorticoid-suppression of NF-κB-mediated
preosteoclast Pdgfb transcription. 3) Examine efficacy of increasing preosteoclast PDGF-BB for preventing
glucocorticoid-suppression of skeletal angiogenesis. Determination of bone-specific factors that regulate
angiogenesis, which is critical to the growing skeleton, will allow targeted drug therapy to treat and/or prevent
osteotoxic side effects of glucocorticoids in children. Furthermore, identification of the mechanism of
glucocorticoid-suppression of angiogenesis will advance our fundamental knowledge and expand future studies
specifically on osteonecrosis, aid in drug-development for therapeutic interventions, and provide insight into
mechanisms of other off-target tissue side effects observed with chronic glucocorticoid usage.

## Key facts

- **NIH application ID:** 10179554
- **Project number:** 1R01AR078793-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Janet Crane
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $360,250
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179554

## Citation

> US National Institutes of Health, RePORTER application 10179554, Role of glucocorticoid-suppression of preosteoclast PDGF-BB in skeletal angiogenesis (1R01AR078793-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10179554. Licensed CC0.

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