Muscle regulation of bone function

肌肉对骨功能的调节

基本信息

批准号：
9889902
负责人：
Gerard Karsenty
金额：
$ 50.05万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889902
关键词：
Acute Address Affect Age B Cell Proliferation Binding Biological Biology Blood Circulation Bone Matrix Bone Resorption Bone remodeling Cell Culture Techniques Cell model Cells Cellular biology Chronic Drops Endocrine Endocrine Glands Environment Exclusion Exercise Feedback Foundations Future GPRC6A gene Goals Homeostasis Hormonal Hormones Human Injections Insulin Interleukin 6 Receptor Interleukin-6 Laboratories Life Metabolic Metabolic Diseases Molecular Mus Muscle Muscle Fibers Muscle function Muscular Atrophy Mutant Strains Mice Myoblasts Organ Osteoblasts Osteocalcin Osteoclasts Osteocytes Pancreas Pathway interactions Peritoneal Physiological Processes Pituitary Gland Play Production Recombinants Regulation Research Rest Role Running Signal Transduction Skeletal Muscle Skeleton Source Structure of beta Cell of islet Suggestion Testing Time Wild Type Mouse Work base blood glucose regulation bone bone cell bone loss bone mass cell type efficacy testing exercise capacity experimental study improved in vivo insulin secretion insulin sensitivity mouse model novel peptide hormone receptor response translational study treadmill

项目摘要

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.

项目概要肌肉衍生分子对骨重塑的影响长期以来一直是一个激烈的话题骨生物学研究。最近我们提供了白细胞介素 6 (IL-6) 合成的提示性证据并在成肌细胞的体循环中分泌，是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二十五个几年前，IL-6 可能调节破骨细胞分化和骨重塑的某些方面。鉴于无论是这些经典的观察还是最近的观察，都出现了一个问题，即是否知道肌肉来源的 IL-6 是年轻人和/或老年人在休息或运动期间骨重塑的重要生物学调节剂老鼠。第二个问题是了解肌肉来源的 IL-6 是否是体内释放的重要调节剂骨钙素的影响，以及这种成骨细胞特异性分泌分子的生物活性。我们打算通过使用几种小鼠模型来解决体内骨生物学的两个相关问题成肌细胞中 IL-6 或其成骨细胞、骨细胞和破骨细胞中受体的细胞特异性缺失。到为了实现这些目标，该应用程序的具体目标是： - 确定肌肉源性 IL-6 在调节体内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量野生型小鼠随着年龄的增长能力。