Project 4 - Role of Osteoprogenitor Hdac3 in Bone Marrow Adiposity

项目 4 - 骨祖细胞 Hdac3 在骨髓肥胖中的作用

• 批准号: 9902290
• 负责人: Meghan E. McGee-Lawrence
• 金额: $ 30.36万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9902290
• 关键词: Adipocytes; Adipose tissue; Affect; Age; Age-Related Bone Loss; Age-Related Osteoporosis; Aging; Amino Acids; Animal Model; Behavior; Bioenergetics; Biological; Biological Assay; Biology; Bone Density; Bone Marrow; Cell Line; Cell Lineage; Cell model; Cell physiology; Cells; Data; Enzymes; Epigenetic Process; Event; Fatty acid glycerol esters; Functional disorder; Genes; Genetic Transcription; Genus Hippocampus; Glucocorticoid Receptor; Glucocorticoids; HDAC3 gene; Human; Immunochemistry; Impairment; In Vitro; Inflammation; Intervention; Knockout Mice; Kynurenine; Lead; Link; Lipids; Marrow; Metabolism; MicroRNAs; Modeling; Molecular; Molecular Profiling; Mus; Muscular Atrophy; Nutrient; Obesity; Osteoblasts; Osteogenesis; Osteopenia; Outcome; Oxides; PPAR gamma; Pathway interactions; Pharmacology; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Population; Prevention; Production; Protein Dephosphorylation; Research; Role; Signal Transduction; Stimulus; Stromal Cells; Testing; Translating; Wild Type Mouse; age related; aged; bone; bone aging; bone loss; bone mass; cell immortalization; conditional knockout; detection of nutrient; experimental study; fracture risk; in vivo; juvenile animal; novel; nutrient deprivation; nutrition; osteoprogenitor cell; prevent; progenitor; skeletal; stem cells; transcription factor

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.

骨量、骨强度和骨髓肥胖在生理和病理生理条件下是相互联系的 包括衰老和营养改变，因为衰老和营养缺乏都会导致骨质减少， 骨髓脂肪增加，增加骨折风险。最近的研究表明，有条件地删除 成骨细胞祖细胞中的表观遗传酶组蛋白脱乙酰基酶3（Hdac 3）模拟这种现象， 骨质减少、骨骼脆弱和骨髓肥胖增加，甚至在幼年动物中也是如此。统一这些 通过观察，初步研究证实，骨髓中Hdac3的表达和活性降低， 来自老年人和老年野生型小鼠的基质细胞（BMSC）衍生的骨祖细胞与 年轻的控制。脂滴形成在老年和年轻的Hdac 3缺失的BMSC来源的细胞中都是丰富的。 成骨细胞培养，初步数据表明，部分是由于脂质储存的机制， 成骨细胞谱系细胞。这种转变的范例表明，骨祖细胞是表观遗传启动 当Hdac3水平下降时，这些细胞可以储存脂质，这些含脂质的细胞构成了一个独特的组成部分， 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- 相关的刺激和上游的有害变化的BMSC和成骨细胞的功能，降低骨密度 增加骨髓脂肪。这项研究的中心假设是，Hdac3控制着 骨祖细胞以骨形成为代价储存脂质的倾向，有助于降低 随着年龄的增长，骨量和骨髓脂肪增加。这条研究路线的意义在于Hdac 3及其 脂质储存的下游调节剂代表了治疗和预防年龄相关性骨损伤的新靶点 损失，可能通过调节营养相关的刺激。这项研究的目的是揭示 Hdac3调节成骨祖细胞中脂质储存的生理和分子机制 随着年龄的增长和营养的改变。动物模型和体外实验用鼠和人的主要和 永生化细胞系将确定年龄、Hdac3表达和增加Hdac3表达的条件之间的关系。 骨髓脂肪和减少骨量。预期结果包括识别与衰老相关的刺激， 抑制骨祖细胞中Hdac 3表达作为预防成骨细胞随年龄的功能障碍的靶点，和 确定骨祖细胞中Hdac3的缺失如何影响与骨直接相关的关键细胞过程 形成和脂质储存。