# Project 4 - Role of Osteoprogenitor Hdac3 in Bone Marrow Adiposity

> **NIH NIH P01** · AUGUSTA UNIVERSITY · 2020 · $303,605

## Abstract

Bone mass, strength, and marrow adiposity are linked in physiological and pathophysiological conditions
including aging and altered nutrition, as both aging and nutrient deprivation lead to osteopenia with a concomitant
increase in bone marrow fat that elevates fracture risk. Recent studies show that conditional deletion of the
epigenetic enzyme histone deacetylase 3 (Hdac3) in osteoblast progenitors mimics this phenomenon, causing
osteopenia, skeletal fragility, and increased marrow adiposity even in young animals. Unifying these
observations, preliminary studies establish that Hdac3 expression and activity are reduced in bone marrow
stromal cell (BMSC)-derived osteoprogenitors from aged humans and aged wild-type mice as compared to
young controls. Lipid droplet formation is abundant in both aged and young Hdac3-depleted BMSC-derived
osteoblast cultures, which preliminary data suggest is due in part to mechanisms of lipid storage by committed
osteoblast lineage cells. This transformative paradigm suggests that osteoprogenitors are epigenetically primed
to store lipids when Hdac3 levels decline, and that these lipid-containing cells constitute a distinct component of
marrow adipose tissue. Preliminary data suggest that age-related suppression of Hdac3 is downstream of aging-
related stimuli and upstream of deleterious changes in BMSC and osteoblast function that reduce bone density
and increase marrow adiposity. The central hypothesis of the proposed research is that Hdac3 governs the
propensity for lipid storage by osteoprogenitors at the expense of bone formation, contributing to decreased
bone mass and increased marrow fat with age. The significance of this line of research is that Hdac3 and its
downstream modulators of lipid storage represent novel targets for treatment and prevention of age-related bone
loss, possibly through modulation of nutrient-related stimuli. The objective of the proposed research is to uncover
the physiological and molecular mechanisms by which Hdac3 regulates lipid storage in osteoblast progenitors
with aging and altered nutrition. Animal models and in vitro experiments with murine and human primary and
immortalized cell lines will define relationships between age, Hdac3 expression, and conditions that increase
marrow fat and decrease bone mass. Expected outcomes include the identification of aging-related stimuli that
suppress expression of Hdac3 in osteoprogenitors as targets for preventing osteoblast dysfunction with age, and
determination of how loss of Hdac3 in osteoprogenitors affects key cellular processes directly related to bone
formation and lipid storage.

## Key facts

- **NIH application ID:** 9902290
- **Project number:** 5P01AG036675-09
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Meghan E. McGee-Lawrence
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $303,605
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902290

## Citation

> US National Institutes of Health, RePORTER application 9902290, Project 4 - Role of Osteoprogenitor Hdac3 in Bone Marrow Adiposity (5P01AG036675-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9902290. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*