Project 4 - Role of Osteoprogenitor Hdac3 in Bone Marrow Adiposity

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.