Effects of Aging on Osteocyte Response to Mechanical Stimulation

衰老对骨细胞对机械刺激反应的影响

基本信息

批准号：
8281078
负责人：
MARK Louis JOHNSON
金额：
$ 30.1万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

项目摘要

Bone is a dynamic organ that is known to adjust in mass, material and architectural properties with respect to the load environment. The progressive decline in muscle mass, sti-ength/performance (sarcopenia) and bone loss (osteopenia/osteoporosis) that occurs with aging suggeste a functional coupling between the diseases. As the osteocyte is thought to be the mechanosensory cell in bone, an age-related reduction in ite ability to respond to load would have significant consequences on bone mass. We have shown that the Wnt/|3-catenin signaling pathway is a critical component of bone responsiveness to mechanical loading and is rapidly activated in osteocytes following the in vivo application of load. Recent data shows that loss of one allele of P-catenin in osteocytes prevents new bone formation in response to mechanical loading. Furthermore, we have provocative preliminary data that muscle derived soluble factor(s) enhance the effecte of loading on the Wnt/p-catenin pathway in osteocytes (see Subproject 1), but that muscle converte from producing bone beneficial factors to producing bone detrimental factors with aging. This project will test the hypothesis that aging alters the osteocyte's ability to respond to mechanical loading. To test this hypotiiesis we propose three specific aims. In Aim 1 we wiil determine the effect of aging on the ability of the osteocyte to respond to mechanical loading. In Aim 2 we will determine the effect of aging on ttie osteocyte sti^in environment. In Aim 3 we will detennine in if muscle inactivation has an affect on the anabolic response of bone and whether this is latered with age. These aims will be accomplished using young (5 mo old), mature (12 mo) and aged (22 mo) mouse models of nonmal and a new Cre mouse we have generated that allows us to temporally and specifically delete genes in osteocytes. In vitro studies using bone and muscle cell model systems and primary cells will be used to dissect the molecular basis for the changes we observe in vivo. Overall these aims will enable us to determine the magnitude of strain necessary to initiate the biological response of Wnt/p-catenin activation, whether aging alters the intrinsic ability of the osteocyte to respond to load and if the osteocyte regulates ite strain environment through p-catenin expression. RELEVANCE (See instructions): The studies proposed in this project are paradigm setting and have the potential to launch a new direction for the study of musculoskeletal diseases and how aging alters these nonnal processes. Knowledge from these studies on how the osteocyte responds to mechanical load and how this response is conditioned by muscle derived factors will produce new targets for drug development to treat sarcopenia and osteoporosis. PROJECT/PERFORMANCE SrTE(

骨骼是一种动态器官，已知可以根据以下方面调整质量、材料和结构特性：负载环境。肌肉质量、强度/性能逐渐下降（肌肉减少症）和随着衰老而发生的骨质流失（骨质减少/骨质疏松症）表明，骨质疏松症与骨质疏松症之间存在功能性耦合。疾病。由于骨细胞被认为是骨骼中的机械感觉细胞，因此年龄相关的骨细胞减少对负荷的反应能力会对骨量产生重大影响。我们已经证明了 Wnt/|3-连环蛋白信号通路是骨对机械负荷和骨反应的关键组成部分在体内施加负载后，骨细胞中的骨细胞迅速被激活。最新数据显示，损失一骨细胞中的 P-连环蛋白等位基因可防止响应机械负荷而形成新骨。此外，我们有令人兴奋的初步数据表明肌肉来源的可溶性因子增强了效果骨细胞中 Wnt/p-catenin 通路的负载（参见子项目 1），但是肌肉从随着年龄的增长，产生骨有益因素和产生骨有害因素。该项目将测试假设衰老会改变骨细胞对机械负荷的反应能力。为了检验这个假设我们提出三个具体目标。在目标 1 中，我们将确定衰老对骨细胞能力的影响响应机械负载。在目标 2 中，我们将确定衰老对骨细胞稳定性的影响环境。在目标 3 中，我们将确定肌肉失活是否会影响合成代谢反应骨骼以及这是否会随着年龄的增长而延迟。这些目标将通过年轻（5个月大）、成熟的人来实现我们生成的非正常小鼠（12 个月）和老年（22 个月）小鼠模型以及新的 Cre 小鼠模型使我们能够暂时且特异性地删除骨细胞中的基因。使用骨和肌肉细胞模型的体外研究系统和原代细胞将用于剖析我们在体内观察到的变化的分子基础。总的来说，这些目标将使我们能够确定启动生物反应所需的应变大小。 Wnt/p-连环蛋白激活的反应，衰老是否会改变骨细胞响应的内在能力负载以及骨细胞是否通过 p-连环蛋白表达调节应变环境。相关性（参见说明）：该项目提出的研究是范式设定，有可能为以下领域开辟新的方向：研究肌肉骨骼疾病以及衰老如何改变这些正常过程。知识来自于这些研究骨细胞如何响应机械负荷以及肌肉如何调节这种响应衍生因素将为治疗肌肉减少症和骨质疏松症的药物开发产生新的目标。项目/绩效 SrTE(