Neuronal control of bone mass by Sirt1

项目摘要-项目#2 与大多数器官相似，骨骼的各种功能受到细胞外 线索、激素和神经递质。骨质量的一种类型的神经元调节是 一种是由神经递质血清素引发的，通过抑制 交感神经系统的活动。这一观察结果提出了关于 调节脑5-羟色胺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Sirt 1是一种 骨质量的神经元控制的转录调节剂。一个广义但适度的 转基因小鼠中Sirt 1表达（TgSirt 1）的增加通过以下方式损害骨量： 抑制骨形成和促进骨吸收。Sirt 1的相反作用 骨重建的两个区室与骨重建的活性增加相关。 交感神经系统（SNS）。另外三项观察结果表明，SNS是一种 Sirt 1的骨骼作用的介导剂。首先，Ucp 1在棕色脂肪中的表达， TgSirt 1小鼠中的儿茶酚胺水平增加。第二，药理学抑制 TgSirt 1小鼠的SNS活性完全恢复了成骨细胞和破骨细胞的数量， 低骨量表型。第三，更直接地，腺病毒介导的 大脑中Sirt 1的缺失会降低SNS活性，并通过增加骨密度来增加骨量。 骨形成和抑制骨吸收。因此，我们的数据表明， Sirt 1通过增加SNS信号来控制骨量。Sirt 1可以通过增加 单胺氧化酶A（MAO-A）的表达，Sirt 1靶点，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 蓝斑的紧张程度本申请旨在鉴定Sirt 1在脑中的作用位点， 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Sirt 1的骨骼效应，以确定脑干、蓝斑是否 或MAO-A表达神经元是Sirt 1调节骨骼肌的特定脑部位， 稳态，并评估MAO-A和Tph 2在Sirt 1- 骨质依赖性调节。

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.