Attenuation of cancellous osteopenia by in vivo loading

通过体内负荷减轻松质性骨质减少

• 批准号: 7132726
• 负责人: Marjolein C van der Meulen
• 金额: $ 27.11万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/7132726
• 关键词: age difference; aging; animal old age; biomechanics; bone; bone regeneration; computed axial tomography; estrogens; histology; infrared spectrometry; injury prevention; interferometry; juvenile animal; laboratory mouse; longitudinal human study; mature animal; mechanical stress; menopause; osteopenia; ovariectomy; skeletal system; tibia

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（由申请人提供）：骨骼质量和承载能力随着年龄的增长以及相关的激素和代谢变化而减少，导致皮质松质部位的骨骼骨折。生物物理刺激可能是对抗与年龄相关的骨量、结构和强度变化的有效疗法。众所周知，动态机械负荷可以调节骨骼质量和结构。然而，人们对松质骨适应机械刺激的机制知之甚少，因为我们对负载和骨形成的大部分知识都是基于皮质适应。我们的总体目标是检验以下假设：应用于松质骨的体内循环机械负荷可以抵消雌激素撤退和衰老引起的骨质减少。为了检验这一假设，我们开发了一种加载装置，可以在体内对小鼠胫骨进行良好控制的生理压缩。具有这种生理负荷的健康小鼠的胫骨干骺端会产生增加的松质骨量。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机械负荷。我们的加载方案将与我们初步研究中使用的相同。对于目标 2，我们将向 6 个月大的小鼠施加受控机械负荷，并证明成骨机械刺激将在雌激素存在的情况下诱导成年小鼠的骨形成。这些老年小鼠已经骨质减少，因此也证明组织基质表面并不是响应机械负荷的限制因素。最后，在目标 3 中，我们将检查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。对于每个目标，长期实验将证明稳态适应性反应，短期实验将重点关注细胞机制。将在胫骨干骺端评估松质结构、材料特性、细胞活性和承载能力。结合起来，这些实验将证明动态机械负荷对于维持和增强松质骨量的功效以及雌激素在此过程中的作用。这些实验将深入了解松质骨适应机械负荷的机制，以及抑制与年龄相关和绝经后骨质流失的策略。