Cross-talk between skeleton and pancreas morphogeneses during development

描述（由申请人提供）：该项目有两个，内在联系，目标。第一个是确定在发育过程中骨和胰腺形态发生之间的交叉调节机制。第二个是评估这种交叉调节是否涉及母体成分。越来越多的研究已经证实，成年期存在葡萄糖和骨代谢的相互作用。一方面，成骨细胞，骨形成细胞，分泌一种激素，骨钙素，调节胰岛素的合成和分泌等过程。另一方面，成骨细胞中的胰岛素信号调节骨钙素的产生及其再吸收介导的活化。因此，在成年期，存在一个前馈调节回路，由此b细胞的胰岛素分泌增强骨钙素的产生和活性，骨钙素反过来促进胰岛素合成。最近，我们发现骨钙素也控制发育中胚胎的b细胞增殖。与成人中存在的骨细胞和b细胞之间的功能串扰相平行，我们假设骨钙素和胰岛素之间的调节回路可能存在于发育过程中，并可能有助于胚胎中骨骼和内分泌胰腺的形成。因此，与对照同窝仔相比，成骨细胞中缺乏胰岛素信号传导的幼崽具有b细胞增殖的减少和骨吸收生物标志物的较低血清水平。骨钙素的另一个最近发现的特征是它能够在怀孕期间穿过胎盘并在胚胎产生自己的细胞之前到达胚胎。因此，母体骨钙素可能在胰腺发育过程中调节胰岛素的产生和B-细胞增殖中起作用。与该假设一致，我们观察到喂食高脂肪饮食的成年Ocn+/-小鼠在从Ocn-/-母亲出生时比从Ocn+/-母亲出生时变得更葡萄糖不耐受。总之，这些新的发现和我们的初步数据提出了前景，母体骨钙素可以启动，或有助于，骨钙素和胰岛素之间的交叉调节，影响骨骼和胰腺的发展。为了证明这一假设，我们提出了以下具体目标：1。确定母体骨钙素是否影响胚胎中胰岛素的产生和b细胞的增殖。测试成骨细胞中的胰岛素信号是否有助于骨钙素在发育过程中调节b细胞增殖3。为了评估骨骼发育是否依赖于胚胎在发育过程中胰岛素的产生，我们在此强调，进行这些研究所需的转基因小鼠模型已经产生，因此实现这些目标可以满足R21项目的时间轴。

DESCRIPTION (provided by applicant): This project has two, intrinsically linked, goals. The first one is to identify cross-regulatory mechanisms between bone and pancreas morphogenesis during development. The second one is to assess whether this cross-regulation involves a maternal component. A growing body of studies has established the existence of a cross-talk of glucose and bone metabolisms during adulthood. On the one hand osteoblasts, the bone-forming cells, secrete a hormone, osteocalcin, regulating insulin synthesis and secretion among other processes. On the other hand, insulin signaling in osteoblasts regulates osteocalcin production and its resorption-mediated activation. Hence, during adulthood there is a feed-forward regulatory loop whereby insulin secretion by b-cells enhances the production and activity of osteocalcin, which in turns promotes insulin synthesis. More recently, we have shown that osteocalcin also controls b-cell proliferation in the developing embryo. Drawing a parallel with the functional crosstalk between bone cells and b-cells existing in adults, we hypothesize that a regulatory loop between osteocalcin and insulin could exist during development and could contribute to the formation of the skeleton and endocrine pancreas in the embryo. Accordingly, pups lacking insulin signaling in osteoblasts have a decrease in b-cell proliferation and lower serum levels of a biomarker of bone resorption compared to control littermates. Another recently identified feature of osteocalcin is its ability to cross the placenta during pregnancy and reach the embryo before it can produce its own. Hence, maternal osteocalcin could play a role in regulating insulin production and b- cell proliferation during pancreas development. In agreement with this hypothesis we have observed that adult Ocn+/- mice fed a high fat diet become more glucose intolerant when they are born from an Ocn-/- mother than from an Ocn+/- mother. Taken together, these novel findings and our preliminary data raise the prospect that maternal osteocalcin could initiate, or contribute to, a cross-regulation between osteocalcin and insulin that influences bone and pancreas development. To demonstrate this hypothesis we propose the following Specific Aims: 1. To determine whether maternal osteocalcin influences insulin production and b-cell proliferation in the embryo 2. To test whether insulin signaling in osteoblasts contributes to the regulation of b-cell proliferation by osteocalcin during development 3. To assess whether skeletogenesis is dependent of the embryonic production of insulin during development We would like to emphasize here that the genetically modified mouse models required to perform these studies have already been generated and therefore that achieving these aims can meet the timeline of a R21 project.