Diffuse microdamage in bone: Direct repair without remodeling

骨骼弥漫性微损伤：直接修复而不重塑

• 批准号: 8206602
• 负责人: MITCHELL B SCHAFFLER
• 金额: $ 16.81万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206602
• 关键词: Acute; Address; Aging; Apoptosis; Area; Back; Biological; Bone Matrix; Bone Regeneration; Bone Tissue; Bone remodeling; Collagen; Deposition; Diffuse; Engineering; Extracellular Matrix; Failure; Fatigue; Fluorescence; Fracture; Healed; Homeostasis; Image; Immunohistochemistry; In Situ; Life; Location; Maintenance; Measures; Mechanics; Mediating; Methods; Microscopic; Minerals; Modeling; Neprilysin; Osteocalcin; Osteoclasts; Osteocytes; Pathway interactions; Physiological; Physiology; Principal Investigator; Process; Production; Property; Raman Spectrum Analysis; Rattus; Reaction; Reporting; Research; Scanning Acoustic Microscopy; Series; Site; Skeleton; Staining method; Stains; Structural Protein; Testing; Time; Tissues; X Chromosome; base; bone; bone cell; dentin matrix protein 1; healing; improved; in vivo; inorganic phosphate; mineralization; novel; osteopontin; prevent; public health relevance; repaired; response; skeletal; ulna

DESCRIPTION (provided by applicant): Microscopic damage is the microstructural consequence of wear and tear (i.e., fatigue) in bone. Bone remodeling can repair the typical linear microcracks that have been reported in bone, and this capability is essential for maintenance of its mechanical integrity. However, recent studies demonstrate that linear microcracks are just one of a range of matrix damage types that result from fatigue in bone. Most other matrix damage processes cause "small crack"-type damage, which are collectively referred to as "diffuse" damage. Diffuse damage is widely observed in the aging skeleton, and like typical linear microcracks it degrades bone material properties, yet the relevance of diffuse damage to bone physiology is not known. Our preliminary studies show that diffuse damage does not activate bone remodeling as do typical microcracks, nor does it cause the local osteocyte apoptosis now known to control the subsequent remodeling response. Rather, osteocytes at diffuse damage sites appear to remain quite healthy. In view of recent discoveries showing osteocytes actively regulate their surrounding matrix, particularly by regulating local mineral deposition, we propose that bone possesses a matrix level "self-repair" mechanism that is distinct from osteoclast-based remodeling. In this process, small ("diffuse") crack damage undergoes direct repair through the actions of osteocytes. We will use the rat in vivo ulnar bending fatigue model to address this question in vivo. In the first studies, discrete regions of diffuse matrix damage will be induced. Changes in the mechanical properties of local regions of diffuse damage and of corresponding areas in non-fatigued bone will be measured using Scanning Acoustic Microscopy. Quantitative back-scattered imaging will be used to examine mineral matrix integrity and the local mineral content in diffuse damage regions, and Raman spectroscopy used to characterize crystal size and mineral and organic composition. In the second series of studies, we will determine whether fatigue selectively elicits changes in the expression of local mineralization-regulating molecules by osteocytes within diffuse damage sites, consistent with a restore local matrix mineral integrity in diffuse damage regions. PUBLIC HEALTH RELEVANCE: It has long been known that bone remodeling can remove and repair the typical microscopic (~100 5m size) cracks that result from wear and tear (i.e., mechanical fatigue) in bone, and thereby help restore strength and prevent fracture. However, there are other types of fatigue damage in the matrix of bone, comprised of much smaller cracks (1-2 5m or smaller) that also weaken bone substantially. We recently discovered that these small cracks are not dealt with by bone remodeling. Thus, their healing must involve other biological mechanisms. In these studies, we will test whether these very small cracks in bone can heal over time through another mechanism than does not involve bone remodeling, and we will also examine how osteocytes, the bone cells that live buried within the bone matrix, might participate in the direct repair of these very small cracks and prevent bone fragility.

描述（由申请人提供）：显微镜损伤是骨骼中磨损（即疲劳）的微观结构后果。骨重塑可以修复骨骼中报道的典型线性微裂纹，并且该能力对于维持其机械完整性至关重要。但是，最近的研究表明，线性微裂纹只是骨骼疲劳引起的一系列基质损伤类型之一。大多数其他矩阵损坏过程会导致“小裂纹”型损坏，这些损害统称为“弥漫”损坏。在老化的骨骼中广泛观察到弥漫性损伤，就像典型的线性微裂纹一样，它降低了骨骼材料的特性，但是弥漫性损害与骨骼生理学的相关性尚不清楚。我们的初步研究表明，弥漫性损伤不会像典型的微裂纹那样激活骨骼重塑，也不会导致局部骨细胞凋亡现在已知可以控制随后的重塑反应。相反，弥漫性损伤部位处的骨细胞似乎仍然很健康。鉴于最近发现的骨细胞积极调节其周围基质，尤其是通过调节局部矿物质沉积，我们建议骨骼具有与基于破骨细胞的重塑不同的基质水平“自我修复”机制。在此过程中，小（“扩散”）裂纹损害通过骨细胞的作用进行直接修复。我们将使用大鼠体内尺骨弯曲疲劳模型在体内解决这个问题。在最初的研究中，将诱导弥漫基质损伤的离散区域。通过扫描声学显微镜测量了弥漫损伤局部区域的机械性能和非凹陷骨区域的相应区域的变化。定量反向散发成像将用于检查矿物质基质完整性和弥漫性损伤区域中的局部矿物质含量，以及用于表征晶体大小以及矿物质和有机成分的拉曼光谱法。在第二系列的研究中，我们将确定疲劳是否有选择地引起量化损伤位点内的骨细胞在局部矿化调节分子表达中的变化，这与弥漫性损伤区域中的局部基质矿物质完整性一致。 公共卫生相关性：长期以来，人们一直知道，骨骼重塑可以去除和修复骨骼磨损（即机械疲劳）导致的典型显微镜（〜100 5m尺寸）裂缝，从而有助于恢复强度并防止骨折。但是，骨骼基质中还有其他类型的疲劳损伤，包括较小的裂缝（1-2个或较小），也大大削弱了骨骼。我们最近发现，这些小裂纹并未通过骨骼重塑处理。因此，它们的愈合必须涉及其他生物学机制。在这些研究中，我们将测试骨骼中这些非常小的裂缝是否可以随着时间的流逝而与不涉及骨骼重塑的其他机制愈合，我们还将研究骨细胞如何直接修复这些非常小的裂纹并防止骨骼脆弱性的骨细胞，即生存的骨细胞。