MICRODAMAGE, OSTEOCYTE INTEGRITY AND BONE REMODELING

据推测，骨组织重塑有助于去除和 替换累积微损伤的密质骨区域 因为疲劳。然而，人们对损害或 在预期的疲劳水平下发生的重塑反应 是正常磨损造成的骨重建单位 “目标”骨显微镜下受损区域未知。 有效定位和去除受损骨对于 保持骨骼完整最近的数据表明 超微结构水平的骨基质损伤占主导地位的早期 人体骨骼的疲劳过程，而不是典型的线性 微裂纹被广泛认为代表了 疲劳过程这种主要的疲劳损伤的作用 激活皮质内重塑过程的模式是 目前未开发。利用我们对尺骨弯曲的改良 Torrance等人（112）的模型，成年大鼠尺骨可在 体内，以启动皮质内再吸收活性。研究还 表明疲劳时骨细胞活力降低， 损伤，并且改变骨细胞完整性的区域可以 与皮质内吸收相关，不依赖于 微损伤拟议的研究将审查a）是否 骨的早期、超微结构水平的疲劳损伤 皮质内重塑，B）骨疲劳如何影响骨细胞 完整性，和c）骨细胞完整性的变化是否是一个 皮质内重塑的决定因素。具体来说，我们将使用 用于三个相关实验的大鼠尺骨疲劳模型： 1)体内疲劳载荷，结合共聚焦显微镜 骨组织形态计量学将用于确定颞 以及矩阵级损伤过程与 皮质内重塑 2)我们将确定骨基质的特定关联 微损伤和骨细胞活力或骨细胞损伤/丧失 生存能力，并检查骨细胞 在疲劳负载的骨中发生退化。骨细胞完整性 相对于局部骨损伤状态，将使用新的 骨细胞活性原位检测方法的发展 （相对于受损的、不能存活的细胞）。 结合原位 细胞化学染色技术和电子显微镜将是 用于辅助评估骨细胞的机制 退化一个具体的重点将是以下问题： 细胞凋亡是骨细胞对疲劳反应的特征。 3)我们将确定空间和时间上的关联 皮质内吸收与存活/非存活骨细胞之间的关系， 结合了一项研究得出的结论。

It is postulated that osteonal remodeling serves to remove and replace regions of compact bone which accumulate microdamage due to fatigue. However, little is known about the damage or remodeling responses which occur at the levels of fatigue expected to result from normal wear and tear. How bone remodeling units "target" microscopically damaged areas of bone is unknown. Effective targeting and removal of damaged bone is essential for maintaining skeletal integrity. Recent data indicates that ultrastructural-level bone matrix damage dominates the early fatigue process in human bone, rather than the typical linear microcracks which have been widely thought to represent primary fatigue process. The role of this predominant fatigue damage mode on activation of intracortical remodeling processes is currently unexplored. Using our modification of the ulnar bending model of Torrance et al (112), adult rat ulnae can be fatigued in vivo, to initiate intracortical resorption activity. Studies also suggest that decreased osteocyte viability occurs with fatigue and injury, and that areas of altered osteocyte integrity can be associated with intracortical resorption, independent Of microdamage. The proposed studies will examine a) whether early, ultrastructural level fatigue damage in bone initiate intracortical remodeling, b) how bone fatigue affects osteocyte integrity, and c) whether changes in osteocyte integrity are a determinant of intracortical remodeling. Specifically, we will use the rat ulnar fatigue model for three interrelated experiments: 1) In vivo fatigue loading, combined with confocal microscopy and bone histomorphometry will be used to determine temporal and spatial associations of matrix-level damage processes with intracortical remodeling. 2) We will determine the specific associations of bone matrix microdamage and osteocyte viability or osteocyte injury/loss of viability, and examine the mechanism by which osteocyte degeneration occurs in fatigue loaded bone. Osteocyte integrity relative to local bone damage state will be assessed using a newly developed methods for in situ detection of osteocyte viability (versus injured, nonviable cells). A combination of in situ cytochemical staining techniques and electron microscopy will be used secondarily to assess the mechanism of osteocyte degeneration. A specific focus will be on the question of whether apoptosis is characteristic of the response of osteocytes to fatigue. 3) We will determine the spatial and temporal associations between intracortical resorption and viable/nonviable osteocytes by combinin a roaches from the recedin studies.