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Attenuation of cancellous osteopenia by in vivo loading

通过体内负荷减轻松质性骨质减少

基本信息

批准号：
7434480
负责人：
Marjolein C van der Meulen
金额：
$ 23.97万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2010-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Skeletal mass and load-bearing capacity diminish with aging and the associated hormonal and metabolic changes, contributing to skeletal fractures at corticocancellous sites. Biophysical stimuli may be an effective therapy to counter age-related changes in bone mass, structure and strength. Dynamic mechanical loading is known to regulate skeletal mass and structure. However, little is known about the mechanisms of cancellous bone adaptation to mechanical stimuli, as our the majority of our knowledge of loading and bone formation is based on cortical adaptation. Our overall goal is to test the hypothesis that in vivo cyclic mechanical loading applied to cancellous bone counteracts the osteopenia induced by estrogen withdrawal and aging. To test this hypothesis we have developed a loading device to administer well-controlled physiological compression to the mouse tibia in vivo. Increased cancellous bone mass is produced in the tibial metaphysis of healthy mice with this physiological loading. We now propose to examine the interaction of mechanical loading with estrogen-deficiency and aging. In Aim 1, we will apply controlled mechanical loads to the tibiae of 10-week old mice following ovariectomy. Our loading protocol will be identical to that used for our preliminary studies. For Aim 2, we will apply controlled mechanical loads to 6-month old mice and demonstrate that osteogenic mechanical stimuli will induce bone formation in adult mice in the presence of estrogen. These older mice will already be osteopenic and, therefore, also demonstrate that tissue substrate surface is not the limiting factor in responding to mechanical loading. Finally, in Aim 3, we will examine whether estrogen-deficiency reduces the sensitivity of 6-month old mice to osteogenic loading. For each aim, long-term experiments will demonstrate the steady-state adaptive response and short-term experiments will focus on the cellular mechanisms. Cancellous architecture, material properties, cellular activity and load bearing capacity will be assessed in the tibial metaphysis. Combined, these experiments will demonstrate the efficacy of dynamic mechanical loads for maintaining and enhancing cancellous bone mass and the role of estrogen in this process. These experiments will provide insights into the mechanisms whereby cancellous bone adapts to mechanical loading and into strategies for inhibiting age-related and postmenopausal bone loss.

描述（由申请方提供）：骨骼质量和承重能力随着年龄的增长以及相关的激素和代谢变化而减少，导致皮质松质骨部位的骨骼骨折。生物物理刺激可能是一种有效的治疗方法，以对抗与年龄相关的骨量，结构和强度的变化。已知动态机械负荷调节骨骼质量和结构。然而，很少有人知道松质骨适应机械刺激的机制，因为我们的大多数知识的负载和骨形成是基于皮质适应。我们的总体目标是检验这一假设，即在体内施加于松质骨的周期性机械载荷抵消了雌激素戒断和衰老引起的骨质减少。为了验证这一假设，我们开发了一种加载装置，用于在体内对小鼠胫骨进行良好控制的生理压缩。在这种生理负荷下，健康小鼠胫骨干骺端的松质骨质量增加。我们现在建议研究机械负荷与雌激素缺乏和衰老的相互作用。在目标1中，我们将在卵巢切除术后对10周龄小鼠的胫骨施加受控的机械载荷。我们的装载方案将与我们初步研究中使用的方案相同。对于目标2，我们将对6个月大的小鼠施加受控的机械负荷，并证明在雌激素存在下，成骨机械刺激将诱导成年小鼠的骨形成。这些年龄较大的小鼠已经骨质减少，因此也证明组织基质表面不是响应机械负荷的限制因素。最后，在目标3中，我们将研究雌激素缺乏是否会降低6个月大的小鼠对成骨负荷的敏感性。对于每一个目标，长期实验将证明稳态适应性反应和短期实验将集中在细胞机制。将评估胫骨干骺端的松质骨结构、材料特性、细胞活性和承载能力。结合这些实验，将证明动态机械负荷对维持和增强松质骨质量的功效以及雌激素在此过程中的作用。这些实验将为松质骨适应机械负荷的机制和抑制年龄相关性和绝经后骨丢失的策略提供见解。