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 与大多数器官相似，骨骼的各种功能都受到细胞外物质的影响。 线索、激素和神经递质。骨量的一种神经元调节是 一种由神经递质血清素引发的过程，通过抑制 交感神经系统的活动。这一观察结果引发了关于 调节大脑血清素积累和儿茶酚胺的转录机制 合成。在解决这个问题时，我们发现组蛋白脱乙酰酶 Sirt1 是一个 骨量神经元控制的转录调节剂。概括但适度 转基因小鼠中 Sirt1 表达（TgSirt1）的增加会通过以下方式损害骨量： 抑制骨形成并促进骨吸收。 Sirt1 的相反作用 骨重塑的两个区室与骨活性的增加相关 交感神经系统（SNS）。另外三个观察表明 SNS 是一种 Sirt1 骨骼行为的调节者。首先，Ucp1在棕色脂肪中的表达和 TgSirt1 小鼠的儿茶酚胺水平升高。二、药理抑制作用 TgSirt1 小鼠中的 SNS 活性完全恢复了成骨细胞和破骨细胞的数量，并挽救了 这些动物的低骨量表型。第三，也是更直接的，腺病毒介导的 大脑中 Sirt1 的缺失会降低 SNS 活性，并通过增加骨量来增加骨量。 骨形成和抑制骨吸收。因此，我们的数据表明神经元 Sirt1 通过增加 SNS 信号传导来控制骨量。 Sirt1 可以通过增加 单胺氧化酶 A (MAO-A) 的表达，这是 Sirt1 的一个靶标，可降低血清素水平 大脑和/或通过抑制脑干中的血清素合成或通过调节交感神经 蓝斑处的音调。该应用程序旨在识别 Sirt1 在大脑中的作用位点， 成骨细胞。老化骨骼中的骨细胞和破骨细胞，从遗传学上证明 SNS介导Sirt1的骨骼效应，以确定是否脑干、蓝斑 或 MAO-A 表达神经元是 Sirt1 调节骨骼的特定大脑位点 稳态并评估 MAO-A 和 Tph2 在 Sirt1- 中各自的贡献 骨量的依赖性调节。