# Regulation of Osteoblasts by ACTH and VEGF

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

We are studying how osteoblast death due to glucocorticoids (GCs) is counteracted by vascular
endothelial growth factor (VEGF). Developing osteoblasts express the ACTH receptor, and osteoblasts
express VEGF in response to the adrenocorticotropic hormone (ACTH). Continuous steroid treatment reduces
ACTH production to low levels. In rabbits with high-dose GC, we showed that intermittent ACTH at minimum
doses to elevate ACTH for four hours greatly reduced osteonecrosis. Our recent studies show that osteoblast
growth and differentiation is increased by VEGF. Further, ACTH is one of several factors that regulate VEGF
production in bone. Thus, in bone, as in the adrenal, the actions of ACTH are complex, and systematic work
will be needed to determine how ACTH, VEGF, and other regulatory pathways interact in bone.
 Our hypothesis is that ACTH is a major regulator of bone growth and survival in regions with rapid bone
turnover such as femoral head trabecular bone. The work planned will find quantitative ACTH doses,
currently unknown, that increase bone mass. Work planned we will use a rabbit animal model, and human
cells to assure relevancy to human disease. Our work using mice encountered difficulties in modeling human
bone response; at present the best animal model for osteonecrosis is the rabbit.
 Gaps in understanding include downstream actions of ACTH in bone cells. Interactions of ACTH with
other systems that regulate VEGF, mediated by inflammatory cells, hypoxia, and by additional cytokines. It is
not known how response of bone in vivo varies with the dose or interval of ACTH administration.
 Specific Aim 1 will use methylprednisolone acetate (MPA)-treated rabbits to define the dependency of
osteonecrosis on VEGF synthesis, ACTH concentration, and dose interval. Specifically, we will define
concentration dependency of ACTH effects. We will study effects on VEGF production of varying ACTH
injection, relative to depot MPA alone or in untreated rabbits. ACTH will be injected daily, at 8 AM, at 0.01,
0.03, 0.1, and 0.3 µg/kg, for 28 days. Osteonecrosis, bone turnover, serum ACTH and corticosteroids will be
measured. This will establish the relationship of specific ACTH doses to suppression of osteonecrosis.
Additionally, to define effect of frequency of ACTH administration on efficacy, we will compare the effects of
ACTH at 0.05 or 0.15 µg/kg twice daily versus 0.1 or 0.3 µg/kg once daily.
 Specific Aim 2 will study the mechanism of response of human osteoblasts to ACTH and VEGF in vitro.
To determine whether ACTH provides survival signals in addition to VEGF, we will study the response of
osteoblasts to VEGF, with and without ACTH. Cell proliferation and matrix synthesis will be measured, as well
as production of regulatory cytokines by osteoblasts under normal and hypoxic conditions. Further to define the
VEGF response, we will make osteoblasts with VEGF receptors -1 and -2 (flt-1 and flk-1) eliminated. This will
allow ACTH effects to be defined in ...

## Key facts

- **NIH application ID:** 10177859
- **Project number:** 5I01BX002490-07
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Harry Colbert Blair
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-10-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177859

## Citation

> US National Institutes of Health, RePORTER application 10177859, Regulation of Osteoblasts by ACTH and VEGF (5I01BX002490-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10177859. Licensed CC0.

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