Role of FoxOs in Skeletal Homeostasis- Resubmission

FoxOs 在骨骼稳态中的作用 - 重新提交

• 批准号: 9212784
• 负责人: Maria Jose Almeida
• 金额: $ 32.78万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212784
• 关键词: Acetylation; Adult; Adverse effects; Age; Age-Related Osteoporosis; Aging; Animals; Attenuated; Binding; Bone Resorption; Cell Line; Cells; DNA; Deacetylase; Deacetylation; Degenerative Disorder; Development; Disease; Equilibrium; FOXO1A gene; Foundations; Funding; Generations; Genes; Genetic Transcription; Genetic study; Grant; Growth Factor; Homeostasis; Human; Hydrogen Peroxide; In Vitro; Inherited; Knowledge; Laboratories; Link; Maintenance; Malignant Neoplasms; Mammals; Mediating; Mitochondria; Mus; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Organ; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Play; Population Heterogeneity; Production; Proteins; Reactive Oxygen Species; Resveratrol; Role; Seminal; Signal Transduction; Testing; Tissues; Up-Regulation; WNT Signaling Pathway; Work; age effect; age related; attenuation; beta catenin; bone; bone cell; bone loss; bone mass; catalase; deprivation; ethnic diversity; fracture risk; genome-wide analysis; in vivo; mouse model; mutant; non-genetic; novel therapeutics; osteoclastogenesis; osteoporosis with pathological fracture; osteoprogenitor cell; overexpression; prevent; progenitor; protein B; protein function; public health relevance; skeletal; stressor; therapeutic target; therapy development; transcription factor

 DESCRIPTION (provided by applicant): Wnt/β-catenin signaling is indispensable for bone formation and the maintenance of bone mass in animals and humans. Compromised Wnt signaling plays a pathogenetic role in the development of the acquired forms of osteoporosis - not just the hereditary forms. Likewise, a decline in NAD+, Sirt1 activity and mitochondria ATP production have been implicated in several age related diseases. FoxO transcription factors attenuate Wnt signaling in lineage-committed osteoblast progenitors and, thereby, restrain their proliferation and the supply of matrix synthesizing osteoblasts. This results from the binding of FoxOs to β-catenin and the sequestration of β-catenin away from TCF-mediated transcription. Deacetylation of FoxOs by Sirt1 attenuates the binding of FoxOs to β-catenin. Thus, Sirt1 in osteoprogenitor cells increases Wnt signaling and bone formation. In addition, Wnt signaling increases ATP production via a Sirt1-dependent mechanism while FoxOs decrease ATP production. FoxOs also act in osteoclast progenitors to restrain osteoclastogenesis. This effect results from direct binding of FoxOs to DNA and upregulation of catalase gene transcription. Sirt1 stimulates FoxO-mediated transcription in osteoclast progenitors, thereby inhibiting osteoclastogenesis. The above observations form the foundation of the hypothesis that Sirt1 increases osteoblastogenesis and decreases osteoclastogenesis by deacetylating FoxOs in the respective progenitors. The age-dependent decrease in Sirt1 activity contributes to the pathogenesis of involutional osteoporosis, by tilting the balance between bone formation and resorption, in favor of the latter. Activation of Sirt1 can ameliorate these effects and may, thus, represent a rational therapeutic target for the management of osteoporosis. The beneficial effects of Sirt1 on osteoblastogenesis are amplified by increased ATP production. To test this hypothesis we will investigate the role of FoxO deacetylation in the effects of Sirt1 on bone formation and resorption using mice in which the endogenous FoxO1, 3 and 4 in osteoblast or osteoclast progenitors are replaced with FoxO1 acetylation mutant proteins; or Sirt1 is overexpressed in the presence or absence of FoxOs (Aim 1). In addition, we will examine whether stimulation of Sirt1 antagonizes the adverse effects of aging on bone using mice in which Sirt1 is overexpressed in osteoblast or osteoclast progenitors (Aim 2). Finally, we will perform in vitro studies to determine the contribution of mitochondria ATP production to osteoblastogenesis and the mechanisms via which FoxOs, Sirt1 and Wnt signaling modulate mitochondria function. This work should advance knowledge of how aging decreases bone mass. Furthermore, it should suggest novel therapies to optimize the treatment of osteoporosis.

 描述（由申请人提供）：Wnt/β-连环蛋白信号传导对于动物和人类的骨形成和骨量维持是必不可少的。受损的Wnt信号传导在获得性骨质疏松症的发展中起着致病作用-而不仅仅是遗传性形式。同样，NAD+、Sirt 1活性和线粒体ATP产生的下降与几种年龄相关疾病有关。FoxO转录因子减弱谱系定向成骨细胞祖细胞中的Wnt信号传导，从而抑制其增殖和基质合成成骨细胞的供应。这是由于FoxOs与β-连环蛋白的结合以及β-连环蛋白从TCF介导的转录中隔离。Sirt 1对FoxOs的脱乙酰化作用减弱了FoxOs与β-连环蛋白的结合。因此，骨祖细胞中的Sirt 1增加Wnt信号传导和骨形成。此外，Wnt信号通过Sirt 1依赖性机制增加ATP产生，而FoxOs减少ATP产生。FoxO还在破骨细胞祖细胞中起作用以抑制破骨细胞生成。这种效应是由于FoxOs与DNA的直接结合和过氧化氢酶基因转录的上调。Sirt 1刺激FoxO介导的破骨细胞祖细胞转录，从而抑制破骨细胞生成。上述观察结果形成了Sirt 1通过使各自祖细胞中的FoxOs脱乙酰化而增加成骨细胞生成和减少破骨细胞生成的假设的基础。Sirt 1活性的年龄依赖性降低通过使骨形成和再吸收之间的平衡倾斜而有利于后者，从而有助于退行性骨质疏松症的发病机制。Sirt 1的激活可以改善这些影响，因此， 代表了骨质疏松症管理的合理治疗目标。Sirt 1对成骨细胞生成的有益作用通过增加ATP产生而放大。为了验证这一假设，我们将研究FoxO去乙酰化在Sirt 1对骨形成和骨吸收的影响中的作用，使用小鼠，其中成骨细胞或破骨细胞祖细胞中的内源性FoxO 1，3和4被FoxO 1乙酰化突变蛋白取代;或者Sirt 1在FoxOs存在或不存在的情况下过表达（Aim 1）。此外，我们将研究Sirt 1的刺激是否拮抗衰老对骨的不良影响，使用小鼠，其中Sirt 1在成骨细胞或破骨细胞祖细胞中过表达（目的2）。最后，我们将进行体外研究，以确定线粒体ATP产生对成骨细胞生成的贡献，以及FoxOs，Sirt 1和Wnt信号调节线粒体功能的机制。这项工作应该推进衰老如何减少骨量的知识。此外，它应该提出新的疗法来优化骨质疏松症的治疗。