Muscle regulation of bone function

项目摘要 肌源性分子对骨重建的影响长期以来一直是一个热门话题 研究骨骼生物学。最近，我们提供了提示性的证据，白细胞介素-6（IL-6）的合成 在，并分泌在一般循环中的成肌细胞，是一个强大的和积极的调节剂的释放， 骨源性激素骨钙素。此外，骨细胞生物学的经典研究提出了25个 多年前，IL-6可能调节破骨细胞分化和骨重建的某些方面。鉴于 在这些经典的和最近的观察中，出现了一个问题，即知道肌肉来源的 IL-6是年轻人和/或老年人在休息或运动期间骨重建的生物学重要调节剂。 小鼠第二个问题是要知道肌肉来源的IL-6是否是体内释放的重要调节剂， 骨钙素，因此，这种成骨细胞特异性分泌分子的生物活性。我们打算 解决这两个相关的问题，骨生物学在体内，并通过使用几种小鼠模型， 成肌细胞中IL-6或成骨细胞、骨细胞和破骨细胞中IL-6受体的细胞特异性缺失。到 为了实现这些目标，本申请的具体目的是： - 确定肌肉来源的IL-6在体内调节运动反应和骨量中的作用。 - 描述成骨细胞或破骨细胞谱系细胞中IL-6信号传导对骨形成的相对影响。 运动能力和体内骨量。 - 确定重组骨钙素的急性或慢性递送是否足以增加运动 随着年龄的增长，野生型小鼠的能力。

Project Summary The influence of muscle derived molecules on bone remodeling has been for a long time a topic of intense research in bone biology. Recently we have provided suggestive evidence that interleukin-6 (IL-6) synthesized in, and secreted in the general circulation by myoblasts, is a powerful and positive regulator of the release of the bone-derived hormone osteocalcin. Moreover, classical studies of bone cell biology had proposed twenty five years ago that IL-6 may regulate osteoclast differentiation and some aspects of bone remodeling. In view of both of these classical and more recent observations, the question arises as to know whether muscle-derived IL-6 is a biologically important regulator of bone remodeling at rest or during exercise, in young and/or older mice. A second question is to know whether muscle-derived IL-6 is a significant regulator in vivo of the release of osteocalcin and therefore of the biological activity of this osteoblast-specific secreted molecule. We intend to address these two related questions of bone biology in vivo and through the use of several mouse models of cell-specific deletion for either IL-6 in myoblasts or its receptor in osteoblasts, osteocytes and osteoclasts. To achieve these goals, the Specific Aims of this application are: - Determine the role of muscle-derived IL-6 in regulating exercise response and bone mass in vivo. - Delineate the relative influence of IL-6 signaling in cells of the osteoblast or the osteoclast lineage on exercise capacity and bone mass in vivo. - Determine whether acute or chronic delivery of recombinant osteocalcin is sufficient to increase exercise capacity in wild-type mice as they age.