Sirtuin/FOXO Signaling in the Regulation of Bone Mass

描述（由申请人提供）：在母体申请中，我们描述了FoxO家族的无处不在的转录因子，它们调节发育和代谢稳态。因此，我们提出研究FoxO蛋白之一fox01在骨稳态控制中的作用及其与Sirtuin或2-catenin的相互作用。然而，fox01已知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。由于这些观察结果，并考虑到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的之外的研究中，我们研究了fox01可能通过其成骨细胞表达发挥的潜在代谢功能。我们发现，从成骨细胞（FoxO1ob-/-小鼠）特异性地删除FoxO1，由于成骨细胞增殖减少，导致成骨细胞数量、骨形成率和骨体积减少。破骨细胞数量不受影响。值得注意的是，许多foxo10ob -/-小鼠在断奶前死亡。我们发现Foxo1ob-/-小鼠的低血糖和葡萄糖耐量的改善可以解释围产期死亡率。这些影响似乎源于2细胞增殖、胰岛素分泌和胰岛素敏感性的增加。另外的分子和代谢研究表明，fox01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fox01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Esp和骨钙素的表达或活性来调节葡萄糖稳态。为了验证这一假设，我们将通过遗传学手段确定成骨细胞中的FoxO1是否通过Esp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分泌和敏感性。这些研究将为骨骼控制影响葡萄糖稳态的信号的机制提供新的见解。

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.