Project 4 - Role of Osteoprogenitor Hdac3 in Bone Marrow Adiposity

骨量、强度和骨髓肥胖症在生理和病理生理条件下是相关的。 包括衰老和营养改变，因为衰老和营养缺乏都会导致骨量减少，并伴随 骨髓脂肪增加会增加骨折的风险。最近的研究表明，有条件地删除 成骨细胞前体细胞中的表观遗传酶组蛋白脱乙酰基酶3(HDAC3)模仿这种现象，导致 即使在幼年动物中，骨量减少、骨骼脆性和骨髓肥胖症也会增加。将这些统一起来 观察到，初步研究证实，HDAC3在骨髓中的表达和活性降低 老年人和老年野生型小鼠骨髓基质细胞来源的成骨细胞的比较 年轻的控制组。老年和年轻的HDAC3缺失的骨髓间充质干细胞中都有大量的脂滴形成 成骨细胞培养，初步数据表明，这部分是由于承诺的脂质储存机制 成骨细胞系细胞。这一变革性的范式表明，骨祖细胞是表观启动的。 当HDAC3水平下降时储存脂质，这些含脂细胞构成了 骨髓脂肪组织。初步数据表明，与年龄相关的HDAC3抑制是衰老的下游- 骨髓间充质干细胞和成骨细胞功能降低的相关刺激和上游有害变化 并增加骨髓肥胖症。拟议研究的中心假设是HDAC3管理着 骨祖细胞以牺牲骨形成为代价储存脂肪的倾向，导致减少 骨量和骨髓脂肪随年龄增长而增加。这一系列研究的意义在于，HDAC3及其 脂质储存的下游调节剂是治疗和预防年龄相关性骨骼疾病的新靶点 损失，可能是通过调节与营养相关的刺激。这项拟议的研究的目的是揭示 HDAC3调节成骨细胞前体细胞脂质储存的生理和分子机制 随着年龄的增长和营养变化。小鼠和人原代和人的动物模型和体外实验 永生化细胞系将定义年龄、HDAC3表达和条件增加之间的关系 增加骨髓脂肪，减少骨量。预期结果包括确定与衰老相关的刺激 抑制成骨祖细胞中HDAC3的表达作为预防成骨细胞功能障碍的靶点 骨祖细胞中HDAC3的缺失如何影响与骨直接相关的关键细胞过程 形成和储存脂肪。

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.