Muscle regulation of bone function

项目摘要 长期以来，肌源性分子对骨重建的影响一直是一个激烈的话题。 骨生物学研究。最近，我们提供了提示的证据，白介素6(IL-6)合成 在一般循环中由成肌细胞分泌，是释放成肌细胞的强大和积极的调节器 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项 几年前，IL-6可能调节破骨细胞分化和骨重建的某些方面。鉴于…… 无论是这些经典的还是更新的观察，都产生了一个问题，即是否知道肌肉起源于 IL-6是一种重要的生物学调节因子，在静息或运动中对年轻人和/或老年人的骨重建具有重要的调节作用 老鼠。第二个问题是了解肌肉来源的IL-6在体内是否是释放的重要调节因素 骨钙素，从而影响这种成骨细胞特有的分泌分子的生物活性。我们打算 在体内和通过使用几个小鼠模型来解决这两个相关的骨生物学问题 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。至 为了实现这些目标，本应用程序的具体目标是： -确定肌源性IL-6在调节运动反应和体内骨量中的作用。 -描述成骨细胞或破骨细胞系细胞中IL-6信号对 运动能力和体内骨量。 -确定急性或慢性注射重组骨钙素是否足以增加运动 野生型小鼠随年龄增长的能力。

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.