mTOR Signaling and Bone Formation in Aging Skeleton

衰老骨骼中的 mTOR 信号传导和骨形成

• 批准号: 8472433
• 负责人: MARTIN L ADAMO
• 金额: $ 21.19万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8472433
• 关键词: 1,2-diacylglycerol; 70-kDa Ribosomal Protein S6 Kinases; Acetyl-CoA Carboxylase; Acyl Coenzyme A; Age-Related Bone Loss; Aging; Anabolism; Animals; Attenuated; Awareness; Biological Assay; Biology of Aging; Bone Marrow; Bone Morphogenetic Proteins; Calvaria; Cell Aging; Cells; Ceramides; Clinical; DEXA; Data; Development; Diglycerides; Disease; Elderly; Enzymes; Equilibrium; Fatty acid glycerol esters; Future; Health; In Vitro; Individual; Insulin; Intervention; Laboratories; Left; Lipids; Longevity; Mass Spectrum Analysis; Molecular Genetics; Morbidity - disease rate; Mus; Osteoblasts; Osteogenesis; Osteoporosis; Outcome; Outcome Study; Palmitates; Pathologic; Pathway interactions; Phosphatidic Acid; Population; Proto-Oncogene Proteins c-akt; Publishing; Raptors; Resistance; Rodent; Role; Secondary to; Signal Transduction; Sirolimus; Skeleton; Stromal Cells; Technology; Testing; Therapeutic; Tissues; Work; age related; aged; aging population; base; bone; bone cell; bone morphogenetic protein 7; cell age; fatty acid biosynthesis; fatty acid oxidation; gene therapy; genetic manipulation; human FRAP1 protein; in vivo; in vivo Model; inhibitor/antagonist; juvenile animal; lipid biosynthesis; lipid metabolism; mTOR Inhibitor; mTOR inhibition; middle age; mineralization; mortality; novel; osteoblast differentiation; osteogenic; osteoprogenitor cell; skeletal; soft tissue; therapy design; treatment effect

DESCRIPTION (provided by applicant): Age-related lipotoxicity is defined as the accrual of toxic lipid intermediates such as fatty acyl CoA, ceramide, and diacylglycerol which act to inhibit aspects of tissue function. These metabolites accrue due to increased fatty acid biosynthesis, decreased fatty acid oxidation, and/or increased biosynthesis of the specific intermediate or decreased clearance of the specific intermediate. Aging skeleton has been found to accumulate greater amounts of lipid at the expense of mineralizing bone. Published data as well as our preliminary data indicated BMSC osteoblastic differentiation in vitro and new bone formation in vivo are resistant to stimulatory effects of BMP in older mice. Additionally, we have found that BMP-7-induced ectopic bone in old mice contained elevated levels of FAS compared to young mice. Moreover, we observed that the mTOR inhibitor rapamycin (RAPA) inhibits BMP-7-induced osteogenesis and lipogenesis in cultured osteoblast cells from young animals. We hypothesize that toxic lipids accrue in aged bone and that blockade in the accrual of these lipids will restore BMP-7-induced osteoblast differentiation. We also hypothesize that mTOR determines the balance between osteogenesis and lipid accrual in bone cells, and that this balance may shift towards lipid accrual at the expense of bone formation in aging bone. To test these hypotheses, we will first utilize in vitro cultures of osteoprogenitor cells from bone marrow and calvariae of young, middle aged, and old mice to determine whether lipid intermediates accrue to a greater degree in cells from the older animals and to determine whether pharmacologic and molecular genetic interventions designed to directly decrease lipid accrual and to inhibit mTOR will restore basal and BMP-7-induced osteoblast differentiation. In Aim 2, we will utilize an in vivo model of BMP-7-induced ectopic new bone formation to determine whether direct inhibition of lipid accrual will restore the ability of BMP-7 to promote optimal new bone formation in aging mice. Outcome of this work will provide heretofore unavailable data that will illustrate mechanisms of age-related skeletal lipotoxicity, and whether maneuvers which block toxic lipid accrual can restore bone formation. These outcomes will provide the necessary basis for the development of future therapeutics for the treatment of osteoporosis aimed at reducing lipotoxicity.

描述（由申请方提供）：与脂质相关的脂毒性定义为毒性脂质中间体（如脂肪酰辅酶A、神经酰胺和甘油二酯）的增加，这些中间体可抑制 组织功能方面。这些代谢物由于脂肪酸生物合成增加、脂肪酸氧化减少和/或特定中间体的生物合成增加或特定中间体的清除减少而累积。已经发现，老化的骨骼以骨矿化为代价积累了更多的脂质。已发表的数据以及我们的初步数据表明，体外BMSC成骨细胞分化和体内新骨形成对老年小鼠BMP的刺激作用具有抗性。此外，我们发现，与年轻小鼠相比，老年小鼠中BMP-7诱导的异位骨含有升高的FAS水平。此外，我们观察到mTOR抑制剂雷帕霉素（RAPA）抑制BMP-7诱导的成骨和脂肪生成在培养的成骨细胞从年轻的动物。我们推测，有毒脂质积累在老化的骨和这些脂质的积累中的封锁将恢复BMP-7诱导的成骨细胞分化。我们还假设mTOR决定骨细胞中骨生成和脂质累积之间的平衡，并且这种平衡可能以老化骨中骨形成为代价而向脂质累积转移。为了验证这些假设，我们将首先利用体外培养的骨髓骨祖细胞 以及年轻、中年和老年小鼠的颅骨，以确定脂质中间体是否在来自老年动物的细胞中更大程度地积累，并确定设计用于直接减少脂质积累和抑制mTOR的药理学和分子遗传学干预是否将恢复基础和BMP-7诱导的成骨细胞分化。在目标2中，我们将利用BMP-7诱导的异位新骨形成的体内模型来确定直接抑制脂质积累是否会恢复BMP-7促进最佳新骨形成的能力。 衰老小鼠的骨形成。这项工作的结果将提供迄今尚未获得的数据，将说明与年龄相关的骨骼脂毒性的机制，以及是否演习，阻止有毒脂质积累可以恢复骨形成。这些结果将为未来开发旨在降低脂毒性的骨质疏松症治疗方法提供必要的基础。