DISUSE INDUCED OSTEOCYTE HYPOXIA

需要机械负荷来维持成人的骨量。 骷髅。消除这一关键因素(即，停用)会导致 导致局部骨吸收的一系列细胞事件。 然而，去除机械载荷的途径是 转化为骨吸收的机制尚不清楚。最近，我们有 发现停用可在24小时内引起骨细胞缺氧 正在卸货。据我们所知，这是第一次在体内观察到 细胞缺氧对组织机械负荷变化的反应。 众所周知，低氧可引起各种深刻的细胞反应。 (例如，细胞骨架破坏)。因为骨细胞处于理想的位置 监测和响应骨骼的力学环境，我们建议 废用性骨细胞缺氧有可能引发和/或 调节局部骨吸收。此外，衰老还会削弱 耐受低氧的细胞，因此可能放大吸收 进程。我们的一般假设是，每天的机械负荷 骨是抑制骨细胞缺氧所必需的。要检查这一点 假设，我们将使用废用性骨量减少的禽类模型。在这 模型中，我们可以将尺骨暴露到废弃或废弃叠加 每天都要吃药。提出了五个具体目标，其中 我们将证明：1)停用引起骨细胞暂时性缺氧 先于皮质内吸收并在空间上与其相关，2) 抑制骨细胞缺氧的负荷方案也将防止停用 诱导皮质内吸收，3)年龄不会降低 抑制骨细胞缺氧的特定负荷方案，4)有限的 存在必须重新启动加载才能执行以下操作的时间段 成功挽救骨细胞缺氧和骨吸收，5) 年龄减少了这一机会之窗。我们认为这些组织 水平实验将支持 机械负荷和骨细胞缺氧，并将决定是否 这一过程会随着年龄的增长而改变。因此，这些数据将提供基本的 洞察骨细胞如何感知和响应机械刺激 在它们的原生环境中。检查这一过程是如何改变的 随着年龄的增长，将增强我们成功应用这些信息的能力 为了抗击骨丢失病理在我们的 人口老龄化。

Mechanical loading is required to maintain bone mass in the adult skeleton. Removing this critical factor (i.e., disuse) precipitates a series of cellular events resulting in locally mediated bone resorption. However, the pathway by which the removal of mechanical loading is transduced into bone resorption is not understood. Recently, we have found that disuse induces osteocyte hypoxia within 24 hours of unloading. To our knowledge, this is the first in vivo observation of cellular hypoxia in response to altered mechanical loading of a tissue. Hypoxia is known to elicit a variety of profound cellular responses (e.g., cytoskeletal disruption). As osteocytes are ideally situated to monitor and respond to bone's mechanical environment, we suggest that disuse induced osteocyte hypoxia has the potential to initiate and/or mediate local bone resorption. Further, aging diminishes the ability of a cell to withstand hypoxia and may therefore amplify the resorptive process. Our general hypothesis is that daily mechanical loading of bone is required to inhibit osteocyte hypoxia. To examine this hypothesis, we will use the avian model of disuse osteopenia. In this model, we are able to expose the ulna to disuse or disuse superimposed with a daily loading regimen. Five specific aims are proposed in which we will demonstrate that: 1) disuse induced osteocyte hypoxia temporally precedes and is spatially related to intracortical resorption, 2) loading regimens that inhibit osteocyte hypoxia will also prevent disuse induced intracortical resorption, 3) age does not diminish the ability of a given loading regimen to inhibit osteocyte hypoxia, 4) a finite period of time exists in which loading must be re-initiated in order to successfully rescue bone from osteocyte hypoxia and resorption, and 5) age diminishes this window of opportunity. We believe that these tissue level experiments will support a cause and effect relation between mechanical loading and osteocyte hypoxia, and will determine whether this process is altered by aging. The data will thereby provide basic insight toward how osteocytes perceive and respond to mechanical stimuli within their native environment. Examining how this process is altered by aging will enhance our ability to successfully apply this information toward combating bone loss pathologies increasingly prevalent in our aging population.