Remodeling Suppression: Collagen Effects on Fracture Energy

重塑抑制：胶原蛋白对断裂能的影响

• 批准号: 7847557
• 负责人: David B Burr
• 金额: $ 32.89万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847557
• 关键词: Adult; Advanced Glycosylation End Products; Alendronate; Animal Model; Animals; Architecture; Bone Density; Bone Matrix; Bone Tissue; Canis familiaris; Clinical; Collagen; Control Animal; Cyclophosphamide; Data; Diabetes Mellitus; Diaphyses; Distal; Dose; Estrogens; Failure; Femur; Fracture; Gender; Grant; High Pressure Liquid Chromatography; Measurement; Measures; Mechanics; Mediating; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Paget' s Disease; Patients; Play; Postmenopausal Osteoporosis; Postmenopause; Property; Public Health; Pyridoxamine; Rattus; Reaction; Research Infrastructure; Role; Site; Sorbitol; Testing; Time; Tissues; United States National Institutes of Health; Weight; Work; absorption; bisphosphonate; bone; clinically relevant; crosslink; density; deoxypyridinoline; diabetic; diabetic rat; inhibitor/antagonist; mineralization; non-diabetic; prevent; pyridinoline; research study; skeletal; spine bone structure; substantia spongiosa; sugar; treatment duration; vertebra body

DESCRIPTION (provided by applicant): Our objective is to determine the role that collagen cross-linking (both enzymatic- and non- enzymatically-mediated), collagen maturity (alpha/beta CTX), and the accumulation of advanced glycation end-products (AGE's) play in bone's structural and material energy absorption capacity. Aim 1 will determine whether there is a significant accumulation of AGE's in bone following 2 or 3 years treatment with doses of bisphosphonate currently used to treat postmenopausal osteoporosis, or those used to treat Paget's disease. AGE accumulation will be correlated to toughness and normalized energy to failure. This Aim uses dogs that have already been treated and sacrificed, but proposes material property measurements as well as analysis of collagen cross-linking and maturation that were not proposed in our original application. Aim 2 will determine whether diabetic rats, known to accumulate AGE's in bone, show changes in toughness and normalized energy to failure consistent with our hypothesis that AGE accumulation is associated with reduced energy to failure at the tissue and structural levels. Use of two different AGE inhibitors will establish cause and effect, and may provide information about the mechanism of AGE accumulation, as the inhibitors act at different points of the reaction cycle. Aim 3 will allow us to establish the relationship between AGE accumulation and altered mechanical properties in an estrogen-deficient animal model (ovariectomized rats), an established model for post-menopausal osteoporosis. Use of an AGE inhibitor will establish cause and effect between AGE accumulation and bone's material properties (toughness and normalized energy to failure) that may be more relevant to the post-menopausal situation than intact dogs. Acquisition of a new Skyscan 1172 micro-CT as part of an NIH infrastructure grant will allow us to assess changes in trabecular architecture to better characterize trabecular bone properties. It will also allow us to normalize the mechanical data by the plane of smallest BV/TV to prevent weighting by regions of bone with higher density that do not fail. Our work could help to explain the reason for the reduced toughness and normalized energy to failure found with bisphosphonate treatment, and to determine whether it is possible to prevent these changes in patients who are being treated with bisphosphonates. PUBLIC HEALTH NARRATIVE The objective of this proposal is to determine the role that collagen, and the accumulation of advanced glycation end-products, play in the mechanical properties of bone. This has relevance in understanding the fragility of bone that occurs in post-menopausal osteoporosis, and in Type II diabetes.

描述（由申请人提供）：我们的目标是确定胶原蛋白交联的作用（酶 - 和非酶促介导的），胶原蛋白成熟度（Alpha/beta CTX）以及晚期糖化糖化最终产物（年龄）的积累在骨骼的结构和材料吸收能力中发挥作用。 AIM 1将确定在2或3年治疗后，用目前用于治疗绝经后骨质疏松症或用于治疗Paget病的双膦酸盐的剂量治疗2或3年后，骨骼中是否存在大量的年龄积累。年龄的积累将与韧性和归一化能量与失败相关。该目标使用已经被治疗和牺牲的狗，但提出了材料特性测量以及对我们原始应用中未提出的胶原交联和成熟的分析。 AIM 2将确定糖尿病大鼠是否已知会在骨骼中累积年龄的糖尿病大鼠表现出韧性的变化和归一化能量的失败，这与我们的假设一致，即年龄的积累与在组织和结构水平下的能量减少有关。使用两个不同年龄抑制剂的使用将建立因果关系，并可能提供有关年龄积累机理的信息，因为抑制剂在反应周期的不同点作用。 AIM 3将使我们能够在雌激素缺陷的动物模型（Ovariectomized大鼠）中建立年龄积累与改变的机械性能之间的关系，这是一种既定后绝经后骨质疏松症的既定模型。年龄抑制剂的使用将建立年龄累积与骨骼物质特性（韧性和归一化能量到失败）之间的原因和作用，这可能与绝经后情况更相关。作为NIH基础设施赠款的一部分，获得新的Skyscan 1172 Micro-CT的获取将使我们能够评估小梁结构的变化，以更好地表征小梁骨的特性。它还将使我们能够通过最小的BV/TV平面将机械数据归一化，以防止由较高密度的骨骼加权，而密度不会失败。我们的工作可能有助于解释韧性降低和通过双膦酸盐治疗发现失败的归一化能量的原因，并确定是否有可能防止接受双膦酸盐治疗的患者中的这些变化。公共卫生叙事该提案的目的是确定胶原蛋白的作用以及高级糖基化终产物的积累，在骨的机械性能中发挥作用。这与理解骨骼后骨质疏松症以及II型糖尿病中发生的骨骼的脆弱性有关。