Effects of Osteocalcin and Osteopontin on Damage Morphology and Bone Fragility

骨钙素和骨桥蛋白对损伤形态和骨脆性的影响

• 批准号: 8734754
• 负责人: Deepak Vashishth
• 金额: $ 6.12万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734754
• 关键词: Affect; Age; Aging; Area; Bone Matrix; Cadaver; Development; Diffuse; Disease; Dissection; Enzyme-Linked Immunosorbent Assay; Etiology; Evaluation; Fatigue; Femur; Fourier Transform; Fracture; Goals; Grant; Harvest; Hormones; Human; In Vitro; Individual; Knockout Mice; Lasers; Lead; Mechanics; Minerals; Modality; Modification; Morphology; Mus; Osteocalcin; Osteogenesis; Phosphoproteins; Phosphorylation; Property; Proteins; Public Health; Resistance; Risk; Role; Specimen; Staining method; Stains; Testing; Time; Tissue Donors; Transgenic Mice; age related; base; bone; bone mass; bone quality; bone toughness; glycation; improved; long bone; mouse model; notch protein; novel; osteopontin; public health relevance; research study; tibia

DESCRIPTION (provided by applicant): Although lower bone mass is associated with increased bone fragility, studies conducted during the last grant cycle demonstrated that the mode and magnitude of microdamage formation affects bone's resistance to fracture or 'toughness'. Bones from younger donors are superior in toughness and form diffuse damage as the prominent morphology of microdamage. In contrast, bones from older donors predominantly form linear microcracks that coalesce to cause fracture. The basis of this unique association between damage morphology and toughness is not known. Our preliminary studies show for the first time that diffuse damage in bone initiates in the form of dilatational bands between the fused mineralized aggregates. Dilatational bands stain positive for osteocalcin (OC) and osteopontin (OPN). OC and OPN are present in higher amounts in diffuse damage areas than in controls and the deletion of OC or phosphorylation of bone matrix decreases toughness. Because OPN and OC vary with tissue and donor age, and are intimately associated with each other and with bone mineral where dilatational bands and diffuse damage form, the modification and loss of these non-collagenous matrix proteins may determine the damage morphology and bone's propensity to fracture. Thus the overall goal of this project is to investigate the role of OC and OPN in age-related bone fragility. Bones from human cadavers, aging mouse and transgenic (knock-outs-/- & hetrozygotes) mice including OC-/-, OC, OPN-/- OPN, OPN-OC-/- and OPN-OC and their controls will be subjected to mechanical and immunohistochemical evaluations to investigate whether: (H1): The deletion or modification of OC and or OPN in bone increases bone fragility and bone's propensity to form linear microcracks over diffuse damage; (H2) The age-related increase in bone fragility is associated with the modification and loss of OC and/or OPN that co-localize differently with diffuse damage and linear microcracks. Since OC and OPN levels can be manipulated through hormones and mechanical loading, the evidence of their new direct relationship to damage formation and bone fragility will lead to the development of novel modalities for predicting fracture, as well as strategies for improving bone quality and reducing the fracture risk.

描述（由申请人提供）：尽管骨量降低与骨脆性增加有关，但在上一个资助周期进行的研究表明，微损伤形成的模式和程度影响骨的抗骨折性或“韧性”。来自年轻供体的骨在韧性方面上级，并且形成弥漫性损伤作为微损伤的突出形态。相比之下，来自老年捐赠者的骨骼主要形成线性微裂纹，这些微裂纹结合在一起导致骨折。损伤形态和韧性之间这种独特关联的基础尚不清楚。我们的初步研究表明，第一次在骨中的弥漫性损伤开始在融合的矿化聚集体之间的扩张带的形式。骨钙素（OC）和骨桥蛋白（OPN）染色呈阳性。OC和OPN在弥漫性损伤区域中的含量高于对照组，OC的缺失或骨基质的磷酸化降低了韧性。由于OPN和OC随组织和供体年龄而变化，并且彼此密切相关，并且与骨矿物质密切相关，在骨矿物质中形成骨结合带和弥漫性损伤，这些非胶原基质蛋白的修饰和丢失可能决定损伤形态和骨的骨折倾向。因此，本项目的总体目标是研究OC和OPN在年龄相关性骨脆性中的作用。来自人类尸体、老龄小鼠和转基因动物的骨骼包括OC-/-、OC、OPN-/- OPN、OPN-OC-/-和OPN-OC的（敲除-/-和杂合子）小鼠及其对照将进行机械和免疫组织化学评价以研究是否：骨中OC和/或OPN的缺失或修饰增加了骨脆性和骨在弥漫性损伤上形成线性微裂纹的倾向;（H2）骨脆性的年龄相关性增加与OC和/或OPN的改变和损失相关，OC和/或OPN与弥漫性损伤和线性微裂纹不同地共定位。由于OC和OPN水平可以通过激素和机械负荷来操纵，它们与损伤形成和骨脆性的新的直接关系的证据将导致预测骨折的新模式的发展，以及改善骨质量和降低骨折风险的策略。