Neuronal control of bone mass by Sirt1

Sirt1 对骨量的神经元控制

• 批准号: 8934490
• 负责人: STAVROULA KOUSTENI
• 金额: $ 53.81万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8934490
• 关键词: Accounting; Address; Adenoviruses; Adrenergic beta-Antagonists; Adult; Affect; Age-Related Bone Loss; Aging; Animals; Bone Resorption; Bone remodeling; Brain; Brain Stem; Brown Fat; Catecholamines; Cells; Communication; Cues; Data; Endocrine; Enzymes; Epinephrine; Event; Genetic; Goals; Histone Deacetylase; Homeostasis; Hormones; Human; Knowledge; Light; Link; Longevity; Mammals; Mediating; Mediator of activation protein; Metabolic; Modeling; Molecular; Monoamine Oxidase A; Mus; Neurons; Neurotransmitters; Nicotinamide adenine dinucleotide; Norepinephrine; Organ; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Output; Pathway interactions; Phenotype; Physiological; Physiology; Progress Reports; Proteins; Regulation; Selective Serotonin Reuptake Inhibitor; Serotonin; Signal Pathway; Signal Transduction; Sirtuins; Site; Skeleton; Sympathetic Nervous System; Tissues; Transgenic Mice; Up-Regulation; Urine; base; bone; bone loss; bone mass; bone strength; cofactor; extracellular; improved; locus ceruleus structure; mind control; overexpression; research study; skeletal

Project Summary – Project #2 Similar to most organs, the various functions of the skeleton are influenced by extracellular cues, hormones and neurotransmitters. One type of neuronal regulation of bone mass is the one initiated by the neurotransmitter serotonin that favors bone mass accrual by inhibiting the activity of the sympathetic nervous system. This observation raises questions about the transcriptional mechanisms regulating brain serotonin accumulation and catecholamine synthesis. In addressing this question we have found that the histone deacetylase Sirt1 is a transcriptional modulator of the neuronal control of bone mass. A generalized but modest increase in Sirt1 expression (TgSirt1) in transgenic mice compromises bone mass by suppressing bone formation and by promoting bone resorption. The opposite effects of Sirt1 on the two compartments of bone remodeling correlate with an increase in the activity of the sympathetic nervous system (SNS). Three additional observations implicated the SNS as a mediator of the skeletal actions of Sirt1. First, Ucp1 expression in brown fat and catecholamine levels are increased in TgSirt1 mice. Second, pharmacological inhibition of the SNS activity in TgSirt1 mice fully restores osteoblast and osteoclast numbers and rescues the low bone mass phenotype of these animals. Third, and more directly, adenovirus-mediated deletion of Sirt1 in the brain decreases SNS activity and increases bone mass by increasing bone formation and suppressing bone resorption. Hence, our data suggest that neuronal Sirt1 controls bone mass by increasing SNS signaling. Sirt1 may do so by increasing expression of monoamine oxidase A (MAO-A), a Sirt1 target that reduces serotonin levels in the brain and/or by suppressing serotonin synthesis in the brainstem or by modulating sympathetic tone in the locus coeruleus. This application intends to identify Sirt1 site(s) of action in the brain, osteoblasts. osteocytes and osteoclasts in the aging skeleton, to demonstrate genetically that the SNS mediates the skeletal effects of Sirt1, to determine whether brainstem, locus coeruleus or MAO-A-expressing neurons is the specific brain site(s) through which Sirt1 regulates skeletal homeostasis and to evaluate the respective contribution of MAO-A and Tph2 in the Sirt1- dependent regulation of bone mass.

项目摘要 - 项目＃2 与大多数器官类似，骨骼的各种功能受细胞外影响 提示，激素和神经递质。骨骼质量的一种神经元调节是 神经递质羟色胺发起的一种，通过抑制骨质量的精度 交感神经系统的活性。这种观察提出了有关 转录机制调节脑血清素积累和儿茶酚胺 合成。在解决这个问题时，我们发现组蛋白脱乙酰基酶SIRT1是一个 骨量神经元控制的转录调节剂。广义但谦虚 转基因小鼠中SIRT1表达（TGSIRT1）的增加会损害骨骼质量 抑制骨形成并促进骨骼分辨率。 SIRT1对 骨头重塑的两个隔室与活动的增加相关 交感神经系统（SNS）。另外三个观察结果将SNS作为一个 SIRT1骨骼动作的中介。首先，UCP1在棕色脂肪和 TGSIRT1小鼠的儿茶酚胺水平升高。第二，药物抑制 TGSIRT1小鼠中的SNS活动完全恢复成骨细胞和破骨细胞数量并营救 这些动物的低骨质量表型。第三，更直接，腺病毒介导 SIRT1在大脑中的删除可降低SNS活性，并通过增加骨骼质量 骨形成并抑制骨骼分辨率。因此，我们的数据表明神经元 SIRT1通过增加SNS信号传导来控制骨骼。 SIRT1可以通过增加来做到这一点 单胺氧化物A（MAO-A）的表达，SIRT1靶标可降低5-羟色胺水平 大脑和/或通过抑制脑干中的5-羟色胺合成或通过调节同情 基因座的音调。该应用程序打算识别大脑中的SIRT1站点， 老化骨骼中的骨细胞和破骨细胞，以证明这一点 SNS介导了SIRT1的骨骼效应，以确定脑干，位点层次是否存在 或表达MAO-A的神经元是特定的大脑部位，SIRT1调节骨骼 稳态并评估MAO-A和TPH2在SIRT1-中的相对贡献 骨质的依赖调节。