Regulation of osteocalcin secretion and its therapeutic implication

项目摘要-项目#1 骨源性激素骨钙素调节的生理过程的数量和多样性 提出了体内骨钙素分泌调节的问题。此外，循环中的二氧化碳浓度 在小鼠、马、猴子和人类的生命早期，骨钙素的急剧下降提高了 关于增加老年动物体内这种荷尔蒙的循环水平是否能纠正至少 第二部分，衰老影响骨钙素调节生理过程的表现。为了支持这一点 假设，我们已经收集了骨钙素确实可以挽救与年龄相关的下降的证据 在肌肉功能和认知功能方面。以更全球化的方式解决提出的问题 在上面，我们寻找了一种骨钙素分泌的调节器，它的生物学可以用来证明 增加骨钙素的分泌可以纠正一些有害的衰老表现。在表演中 在这一努力中，我们积累了强有力的初步证据，表明神经元来源的谷氨酸进入 成骨细胞，通过竞争性抑制γ-谷氨酰羧基酶，允许释放 成骨细胞中未羧化的骨钙素。我们现在想要1)证明这一现象的细胞特异性 机制，2)测试该机制是否可以被利用来拯救至少在过去的表现中 由于骨钙素正常增强的生理功能的下降而引起的衰老。要实现 这些重叠目标本应用程序的具体目标是： 在体内证实，它是通过其在成骨细胞系细胞中的表达来影响GLAST的 非羧化形式的骨钙素在全身循环中的释放。 测试成骨细胞或骨细胞过度表达Glast是否会改善能量消耗 小鼠糖代谢、运动适应、认知功能和生育力 OCN版本。

Project Summary – Project #1 The number and diversity of the physiological processes regulated by the bone-derived hormone osteocalcin raise the question of the regulation of osteocalcin secretion in vivo. Moreover, the fact that circulating levels of osteocalcin decrease so steeply in mice, horses, monkeys, and humans relatively early during life raises the question as to whether increasing circulating levels of this hormone in older animals could correct at least in part, manifestations of aging affecting the physiological process regulated by osteocalcin. In support of this hypothesis, we have already gathered evidence that osteocalcin can indeed rescue the age-related decrease in muscle functions and cognitive functions. To address in a more global manner the questions presented above we searched for a regulator of osteocalcin secretion whose biology could be harnessed to demonstrate that increasing osteocalcin secretion could correct some deleterious manifestations of aging. In performing this endeavor we have accumulated strong preliminary evidence that neuron-derived glutamate enters osteoblasts and, through competitive inhibition of the gamma-glutamyl carboxylase, allows the release of uncarboxylated osteocalcin from osteoblasts. We now want to 1) demonstrate the cell-specificity nature of this mechanism, 2) test whether this mechanism can be harnessed to rescue at least in past manifestations of aging caused by a decrease in the physiological functions that osteocalcin normally enhance. To achieve these overlapping goals the Specific Aims of this application are:  Establish in vivo that it is through its expression in cells of the osteoblast lineage that Glast influences the release of the uncarboxylated form of osteocalcin in the general circulation.  Test whether overexpressing Glast in osteoblasts or osteocytes would improve energy expenditure, glucose metabolism, adaptation to exercise, cognitive functions and fertility in aging mice by favoring OCN release.