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，事实上， 骨钙素在小鼠、马、猴和人类生命早期急剧下降， 一个问题是，在老年动物中，这种激素的循环水平的增加是否可以至少在 部分，衰老影响骨钙素调节的生理过程的表现。为支持这一 假设，我们已经收集到的证据表明，骨钙素确实可以挽救与年龄相关的减少 肌肉功能和认知功能。以更全面的方式处理 在上文中，我们寻找骨钙素分泌的调节剂，其生物学特性可以用来证明 增加骨钙素的分泌可以纠正一些老化的有害表现。履行 这项奋进我们已经积累了强有力的初步证据，神经元衍生的谷氨酸进入 通过竞争性抑制γ-谷氨酰羧化酶，允许释放 成骨细胞的未羧基化骨钙素。我们现在想1）证明这种细胞特异性的本质 机制，2）测试是否可以利用这种机制来拯救至少在过去的表现形式， 由骨钙素通常增强的生理功能下降引起的衰老。实现 这些重叠的目标，本申请的具体目标是： 在体内证实Glast是通过在成骨细胞谱系中的表达影响 在全身循环中释放未羧基化形式的骨钙素。 测试在成骨细胞或骨细胞中过表达Glast是否会改善能量消耗， 糖代谢、运动适应、认知功能和生育能力的影响 OCN释放

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.