Attenuation of cancellous osteopenia by in vivo loading

描述(申请人提供)：骨骼质量和承载能力随着年龄的增长而减少，以及相关的激素和代谢变化，导致皮质松质细胞部位的骨骼骨折。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治疗方法。众所周知，动态机械负荷可以调节骨骼质量和结构。然而，对松质骨对机械刺激的适应机制知之甚少，因为我们大多数关于负荷和骨形成的知识都是基于皮质适应的。我们的总体目标是验证这样的假设，即在体内对松质骨施加循环机械载荷可以抵消雌激素停用和衰老引起的骨量减少。为了验证这一假设，我们开发了一种加载装置，在活体内对小鼠胫骨进行良好控制的生理加压。在这种生理负荷下，健康小鼠的胫骨干骺端产生更多的松质骨量。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，我们将在卵巢切除后对10周龄小鼠的胫骨施加受控机械载荷。我们的装载方案将与我们初步研究使用的方案相同。对于目标2，我们将对6个月大的小鼠施加受控的机械载荷，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。这些年长的小鼠将已经是骨量减少的，因此也证明了组织底物表面不是对机械负荷反应的限制因素。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，长期实验将演示稳态适应性反应，短期实验将重点放在细胞机制上。松质骨结构、材料特性、细胞活性和承载能力将在胫骨干骺端进行评估。结合这些实验，这些实验将证明动态机械负荷在维持和增加松质骨量方面的有效性，以及雌激素在这一过程中的作用。这些实验将为松质骨适应机械负荷的机制以及抑制年龄相关和绝经后骨丢失的策略提供洞察力。

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.