Sirtuin/FOXO Signaling in the Regulation of Bone Mass

Sirtuin/FOXO 信号在骨量调节中的作用

• 批准号: 7808346
• 负责人: STAVROULA KOUSTENI
• 金额: $ 64.28万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2011-09-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808346
• 关键词: Affect; Biology; Cell Proliferation; Cells; Development; Endocrine; Energy Metabolism; Family; Feedback; Funding; Genes; Genetic; Homeostasis; Hormones; Hypoglycemia; Insulin Resistance; Liver; Mammals; Metabolic; Molecular; Mus; Mutation; Obesity; Organ; Osteoblasts; Osteocalcin; Osteoclasts; Osteogenesis; Pancreas; Parents; Perinatal; Phenotype; Principal Investigator; Protein Tyrosine Phosphatase; Proteins; Recovery; Regulation; Role; Signal Transduction; Skeleton; Testing; Tissues; United States National Institutes of Health; Weaning; abstracting; base; blood glucose regulation; bone; bone mass; carboxylation; glucose tolerance; improved; insight; insulin secretion; insulin sensitivity; metabolic abnormality assessment; novel; public health relevance; stem; transcription factor

DESCRIPTION (provided by applicant): Component of the application in the parent application we have described the FoxO family of ubiquitous transcription factors which regulate development and metabolic homeostasis. Therein we proposed to study the role of FoxO1, one of three FoxO proteins, and its interaction with Sirtuin or 2-catenin in the control of bone homeostasis. However FoxO1 is known to regulate glucose homeostasis and insulin resistance through its expression in the pancreas and liver. Because of these observations and given the recent realization that osteoblasts are endocrine cells favoring glucose homeostasis, in studies outside the specific aims of the parent application, we examined potential metabolic functions that FoxO1 may exert through its osteoblastic expression. We have found that deletion of FoxO1 specifically from osteoblasts (FoxO1ob-/- mice) decreases osteoblast numbers, bone formation rate and bone volume due to decreased osteoblast proliferation. Osteoclast numbers were not affected. Remarkably, many FoxO1ob-/- mice died before weaning. We found that perinatal lethality could be explained by the fact that Foxo1ob-/- mice were hypoglycemic and displayed improved glucose tolerance. These effects appeared to stem from an increase in 2-cell proliferation, insulin secretion and insulin sensitivity. Additional molecular as well as metabolic studies show that FoxO1, through its expression in osteoblasts, inhibits 2-cell proliferation, insulin secretion and insulin sensitivity. Based on these and additional findings we hypothesize that FoxO1, through its expression in osteoblasts, regulates glucose homeostasis by controlling the expression or activity of two osteoblast-produced proteins Esp and Osteocalcin. To test this hypothesis we will determine through genetic means whether FoxO1 in osteoblasts controls energy metabolism by acting through Esp. We will also examine whether FoxO1 in osteoblasts suppresses insulin secretion and sensitivity by limiting the bioactivity of osteocalcin. These studies will provide novel insights into the mechanisms by which the skeleton controls signals that affect glucose homeostasis. PUBLIC HEALTH RELEVANCE: Component of the application As described in the parent application we deleted Foxo1 specifically from osteoblasts (FoxO1ob-/- mice) and found decreased osteoblast numbers, bone formation rate and bone volume. In addition, Foxo1ob-/- mice were hypoglycemic and displayed improved glucose tolerance. These effects stem from an increase in 2-cell proliferation, insulin secretion and insulin sensitivity. Based on these and additional findings we hypothesize that FoxO1, through its expression in osteoblasts, regulates glucose homeostasis by controlling the expression or activity of two osteoblast-produced proteins Esp and Osteocalcin. These studies will provide novel insights into the mechanisms by which the skeleton controls signals that affect glucose homeostasis under the control of FoxO1.

描述(由申请人提供)：申请的组成部分在父申请中我们已经描述了FoxO家族的普遍存在的转录因子，它们调节发育和代谢动态平衡。在这方面，我们建议研究三种FoxO蛋白之一的FoxO1的作用，以及它与Sirtuin或2-catenin的相互作用在控制骨稳态中的作用。然而，众所周知，FoxO1通过其在胰腺和肝脏中的表达来调节葡萄糖稳态和胰岛素抵抗。由于这些观察，以及最近认识到成骨细胞是有利于葡萄糖稳态的内分泌细胞，在母体应用的特定目标之外的研究中，我们研究了FoxO1可能通过其成骨表达发挥的潜在代谢功能。我们发现从成骨细胞(FoxO1ob-/-小鼠)中特异性缺失FoxO1会减少成骨细胞的数量、骨形成率和骨体积，这是因为成骨细胞的增殖减少了。破骨细胞数量未受影响。值得注意的是，许多FoxO1ob-/-小鼠在断奶前死亡。我们发现，围产期的致死性可以用Foxo1ob-/-小鼠低血糖和糖耐量改善这一事实来解释。这些效应似乎源于2-细胞增殖、胰岛素分泌和胰岛素敏感性的增加。更多的分子和代谢研究表明，FoxO1通过其在成骨细胞中的表达，抑制2-细胞增殖、胰岛素分泌和胰岛素敏感性。基于这些和其他发现，我们假设FoxO1通过其在成骨细胞中的表达，通过控制两种成骨细胞产生的蛋白质ESP和骨钙素的表达或活性来调节葡萄糖的稳态。为了验证这一假说，我们将通过遗传学手段来确定成骨细胞中的FoxO1是否通过ESP来控制能量代谢。我们还将研究成骨细胞中的FoxO1是否通过限制骨钙素的生物活性来抑制胰岛素的分泌和敏感性。这些研究将为骨骼控制影响葡萄糖动态平衡的信号的机制提供新的见解。 公共卫生相关性：应用程序的组件如父应用程序中所述，我们从成骨细胞(FoxO1ob-/-小鼠)中专门删除了Foxo1，发现成骨细胞数量、骨形成率和骨体积减少。此外，Foxo1ob-/-小鼠的血糖水平较低，糖耐量有所改善。这些效应源于2-细胞增殖、胰岛素分泌和胰岛素敏感性的增加。基于这些和其他发现，我们假设FoxO1通过其在成骨细胞中的表达，通过控制两种成骨细胞产生的蛋白质ESP和骨钙素的表达或活性来调节葡萄糖的稳态。这些研究将为骨架在FoxO1控制下控制影响葡萄糖动态平衡的信号的机制提供新的见解。