Sirtuin/FOXO Signaling in the Regulation of Bone Mass

Sirtuin/FOXO 信号在骨量调节中的作用

基本信息

批准号：
7581559
负责人：
STAVROULA KOUSTENI
金额：
$ 35.27万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7581559
关键词：
Acetylation Adult Adverse effects Affect Aging Animal Model Antioxidants Apoptosis Apoptotic Attenuated Biological Biological Models Biomechanics Cell Cycle Arrest Cell Death Cell Differentiation process Cell Line Cell Survival Cell model Cells Complex DNA DNA Repair Daily Data Deacetylase Deacetylation Development Enzymes Family Family member Femur Genes Genetic Genetic Transcription Gonadal Steroid Hormones Growth Homeostasis Homologous Gene Hormonal In Vitro Insulin Lead Link Lipids Longevity Mammals Mediating Metabolic Modality Mus Nematoda Numbers Organism Osteoblasts Osteoclasts Osteoporosis Oxidative Stress Pathway interactions Phosphorylation Physiological Production Property Protein Dephosphorylation Protein Isoforms Proteins Public Health Reaction Reactive Oxygen Species Regulation Role Signal Pathway Signal Transduction Sir2-like Deacetylases Sirtuins Skeletal system Skeleton Stimulus Stress System Testing Thick Time Tissues Transgenic Mice Vertebral column Yeasts angiogenesis base biological adaptation to stress bone bone cell bone loss fly novel strategies progenitor repaired response stressor transcription factor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Bone homeostasis in the adult or aging skeleton, is perturbed by mechanisms that involve decreased defense against oxidative stress and/or increased production of Reactive Oxygen Species (ROS). Remarkably, several molecules that regulate the organism's response to oxidative stress are also shared by signaling cascades that lead to prolongation of lifespan. In bone, and in any other tissue, a variety of metabolic reactions and exogenous agents generate ROS that can damage cellular constituents. Cells counteract the adverse effects of ROS by mechanisms that involve dephosphorylation and subsequent activation of a family of ubiquitous transcription factors known as FOXOs. FOXO1, one of the three FOXO homologs, regulates cell differentiation, promotes either cell survival or apoptosis; and also increases lifespan in model biologic systems. Cellular fate in response to FOXO1 dephosphorylation depends on Sirtuins. Sirtuins are NAD-dependent protein deacetylases which attenuate stress-induced apoptosis and extend lifespan in flies, worms and mammals. The mammalian homolog SIRT1, deacetylates FOXO1, thus shifting FOXO-dependent responses away from cell death and towards cell survival. We have found that FOXO1 and SIRT1 exert direct anti-apoptotic or proliferative effects on osteoblasts and osteoblast precursors. They are also expressed in osteoclasts. SIRT1-dependent deacetylation of FOXO1 is required for its anti-apoptotic effects. Most importantly, FOXO1 haploinsufficiency decreases bone mass and compromises bone microarchitecture in adult mice. Deletion of FOXO1 from osteoblasts results in reduction in osteoblast numbers without affecting osteoclast numbers. Conversely, transgenic mice expressing SIRT1 show enhanced deacetylation of FOXO1 in bone, increased bone mass in the spine and femur and increased osteoblast but decreased osteoclast numbers. Finally, FOXO1 physically associates with ¿-catenin, a key component of the Wnt signaling pathway, to form a functional complex. Oxidative stress increases FOXO1-mediated transcription of anti-oxidant enzymes; and attenuates both the anti-osteoclastogenic and the osteoblastogenic effects of ¿-catenin-mediated transcription in cells of the osteoblastic lineage. In studies to be conducted in this proposal, we will test the hypothesis that SIRT1/FOXO1 signaling is activated in response to physiological levels of oxidative stress to protect bone mass and preserve bone homeostasis. An interaction between this pathway and ¿-catenin may enhance FOXO1-mediated transcription and/or regulate the anti-osteoclastogenic properties of ¿-catenin. In this proposal we will determine the role of FOXO1 in osteoblast function. We will also elucidate the role of SIRT1 by itself or as an activator of FOXO1 signaling in bone. Finally, we will examine whether FOXO1 regulates the anti-osteoclastogenic actions of ¿-catenin. These studies will provide for the first time a link between pathways that regulate oxidative stress, longevity and skeletal homeostasis under the control of the Sirtuin/FOXO system. Treatment modalities aimed at restoring FOXO deacetylation and phosphorylation may form the basis for a novel approach to osteoporosis therapy. PUBLIC HEALTH RELEVANCE. In bone, and in any other tissue, a variety of metabolic reactions and exogenous agents generate Reactive Oxygen Species (ROS) that can damage cellular constituents. Cells counteract the adverse effects of ROS by mechanisms that involve the NAD-dependent protein deacetylase SIRT1 and the transcription factor FOXO1; both of which extend lifespan in flies, worms or mammals. We will test the hypothesis that SIRT1/FOXO1 signaling is activated in response to physiological levels of oxidative stress to protect bone mass and preserve bone homeostasis. An interaction between this pathway and 2-catenin may enhance FOXO1-mediated transcription and regulate the anti-osteoclastogenic properties of 2-catenin.

描述（由申请人提供）：成人或衰老骨骼中的骨稳态受到涉及氧化应激防御能力下降和/或活性氧（ROS）产生增加的机制的干扰。值得注意的是，调节生物体对多种分子的反应。氧化应激也由导致骨骼和任何其他组织寿命延长的信号级联所共享，产生各种代谢反应和外源性物质。 ROS 可以损害细胞成分。细胞通过去磷酸化和随后激活 FOXO 家族（FOXO 的三种同系物之一）的机制来抵消 ROS 的不利影响，调节细胞分化，促进细胞存活。或细胞凋亡；并且还可以延长模型生物系统的寿命，以响应 FOXO1 去磷酸化，而 Sirtuins 是 NAD 依赖性蛋白。哺乳动物同源物 SIRT1 可以使 FOXO1 脱乙酰化，从而将 FOXO 依赖性反应从细胞死亡转向细胞存活。 -对成骨细胞和成骨细胞前体的细胞凋亡或增殖作用它们也在破骨细胞中表达。 FOXO1 的 SIRT1 依赖性脱乙酰作用是其抗细胞凋亡作用所必需的。最重要的是，FOXO1 单倍体不足会降低成年小鼠的骨量并损害骨微结构。从成骨细胞中删除 FOXO1 会导致成骨细胞数量减少，但不会影响离线的转基因细胞数量。表达 SIRT1 的小鼠表现出骨骼中 FOXO1 的脱乙酰作用增强，脊柱和股骨的骨量增加成骨细胞数量增加但破骨细胞数量减少最后，FOXO1 与 ¿ -连环蛋白，Wnt 信号通路的关键组成部分，形成功能性复合物，增加 FOXO1 介导的抗氧化酶的转录，并减弱 ¿ 的抗破骨细胞生成和成骨细胞生成作用。成骨细胞谱系细胞中连环蛋白介导的转录，我们将测试 SIRT1/FOXO1 信号传导响应生理水平的氧化应激而被激活以保护骨量和保持骨稳态的假设。该途径与 ¿ 之间的相互作用-连环蛋白可能增强 FOXO1 介导的转录和/或调节 ¿ 的抗破骨细胞生成特性在本提案中，我们将确定 FOXO1 在成骨细胞功能中的作用，我们还将阐明 SIRT1 本身或作为 FOXO1 信号激活剂在骨中的作用。的这些研究将首次提供在 Sirtuin/FOXO 系统控制下调节氧化应激、寿命和骨骼稳态的途径之间的联系，旨在恢复 FOXO 脱乙酰化和磷酸化的治疗方式可能构成新型治疗的基础。骨质疏松症治疗方法与公共卫生的相关性在骨骼和任何其他组织中，各种代谢反应和外源性物质都会产生活性氧。可以损害细胞成分的物种 (ROS)。细胞通过涉及 NAD 依赖性蛋白脱乙酰酶 SIRT1 和转录因子 FOXO1 的机制来抵消 ROS 的不利影响；这两种酶都可以延长果蝇、蠕虫或哺乳动物的寿命。假设 SIRT1/FOXO1 信号传导响应生理水平的氧化应激而被激活，以保护骨量并维持骨稳态。该途径与 2-catenin 之间存在相互作用。可能增强 FOXO1 介导的转录并调节 2-catenin 的抗破骨细胞生成特性。