Aging and Diabetes-Related Factors Compromising Bone Fracture Resistance

衰老和糖尿病相关因素会影响抗骨折能力

• 批准号: 8253505
• 负责人: Jeffry Stephen Nyman
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253505
• 关键词: Acetylcysteine; Address; Adult; Advanced Glycosylation End Products; Affect; Age; Age-Months; Aging; Antioxidants; Architecture; Asses; Biological; Biological Assay; Biological Markers; Biomechanics; Bone Density; Bone Marrow Cells; Bone Tissue; Cell Culture Techniques; Cells; Characteristics; Clinical; Clinical assessments; Collagen; Diabetes Mellitus; Diagnostic; Drug Delivery Systems; Elderly; Engineering; Extracellular Matrix; Fatigue; Femur; Flushing; Fracture; Glucose; Goals; Growth; Harvest; Heterogeneity; High Pressure Liquid Chromatography; Human; Inbred F344 Rats; Incidence; Incubated; Individual; Life; Marrow; Measurement; Measures; Mechanics; Minerals; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Osteoporosis; Oxidative Stress; Phosphate Buffer; Property; Pyridoxamine; Radial; Rattus; Relative (related person); Research; Resistance; Resistance development; Risk; Rodent; Role; Saline; Solutions; Specimen; Sprague-Dawley Rats; Statistical Models; Structure; Techniques; Testing; Tissues; Translations; Veterans; Vitamin B6; Water; X-Ray Computed Tomography; age related; base; bone; bone cell; bone health; bone quality; bone strength; bone toughness; crosslink; diabetic; drinking water; glycation; improved; inhibitor/antagonist; long bone; male; middle age; mortality; non-diabetic; novel; novel diagnostics; osteoblast differentiation; oxidative damage; pentosidine; prevent; public health relevance; repaired; research study; tool; treatment effect; young adult

DESCRIPTION (provided by applicant): There is an increase in the risk of bone fracture with aging and adult diabetes, and this increase cannot be solely explained by changes in bone mineral density (BMD). One barrier to new diagnostic tools and treatments is that the underlying cause for the disproportionate increase in fracture risk among diabetics and the elderly is currently unknown. Consequently, there is a need to identify the biophysical basis of the age- and diabetes-related changes in bone that decrease fracture resistance, not just bone strength. Addressing this, the proposal aims to determine whether increases in advanced glycation end-products (AGEs) explain the effect of diabetes and aging on the fracture resistance of bone (as characterized by fracture properties) and to determine whether an AGE inhibitor and/or an antioxidant can both improve the quality of bone structure and increase the fracture properties of bone. Aim 1 will determine the role of bone structure, BMD, and AGEs in the effect of Type 2 Diabetes (T2D) and aging on the fracture properties of bone. In the first experiment, bones will be collected from T2D rats and non-diabetic rats at 24 weeks and 32 weeks of age. In the second experiment, bones will be harvested from aging rats at 4 months (young), 12 months (adult), and 24 months (old) of age. All the bones will undergo extensive analysis in order to identify the relative contribution of compositional properties such as BMD and AGEs and structural properties such as moment of inertia to a set of biomechanical properties including traditional measurements of strength and new measurements of fracture toughness and fatigue life. Aim 2 will evaluate how exogenous glycation of collagen affects the fracture properties of bone. This aim investigates whether the direct accumulation of AGEs within the extracellular matrix of bone decreases the fracture resistance of bone and whether the AGE inhibitor pyridoxamine, a B6 vitamin, protects against such a change. With appropriate controls, both human cortical bone and rodent bone will be incubated in diabetic concentrations of glucose with and without the inclusion of pyridoxamine. After quantifying the concentration of pentosidine, a biomarker for AGEs, and BMD, each specimen will be subjected to a mechanical test. In the case of the human bone, tests will determine the effects of increasing AGE on bone strength, post-yield energy dissipation, fatigue life, and crack-initiation & crack-growth toughness. For the rodent bones, tests will determine the effect of increasing AGE on fatigue life and fracture toughness, the ability to resist crack propagation. Aim 3 will assess the efficacy of pyridoxamine and N-acetylcysteine to increase fracture resistance of bone in an aging rat model of T2D through changes in bone structure, BMD, and AGEs. In this translation aim, the role of oxidative stress and AGE accumulation in the aging and diabetic effects on bone will be investigated using these two compounds. Starting at 4 months of age, non-diabetic and T2D rats will drink water, water with pyridoxamine, or water with N-acetylcysteine, an antioxidant. After 4 months, 8 months, and 14 months (aging) of treatment, bones will be harvested for extensive analysis to determine the effects of treatment on the structural, compositional, and biomechanical properties of bone. Additionally, histological and cell culture assays will assess the biological effects of the compounds on oxidative stress and osteoblast differentiation. To achieve these aims, Micro-Computed Tomography will quantify volumetric BMD; high performance liquid chromatography will quantify the concentration of crosslinks and collagen content; and thermal gravimetric analysis will quantify the collagen and mineral fractions as well as water content. Statistical models will determine the relative contribution of the structural and the compositional properties to the fracture properties of bone. This will address the relevance of targeting oxidative stress and AGEs to improve the bone health of Veterans and prevent bone fractures. The long-term goal is to identify the factors affecting the important determinants of fracture resistance and developing accurate diagnostic assessments of fracture risk. PUBLIC HEALTH RELEVANCE: The incidence of bone fractures increases with age and diabetes, and this phenomenon cannot be attributed to a decrease in bone mineral density (BMD). Greater numbers of Veterans are living longer, and many Veterans are developing type 2 diabetes. Thus, the number of fractures will increase. This is a rather significant problem because 1) current clinical tools based on BMD measurements do not necessarily identify individuals at risk of a fracture, 2) fracture resistance is more than just a problem of low BMD and low bone strength, 3) fractures are costly to repair and are associated with a high mortality rate, and 4) current osteoporosis drugs targeted to increasing BMD may not reduce the fracture risk of diabetics. Thus, there is a need to identify new mechanisms that affect the quality of bone tissue. The proposed research therefore explores oxidative stress and the accumulation of non-enzymatic crosslinks as factors underlying the biophysical changes that reduce the fracture resistance of bone.

描述（由申请人提供）： 随着年龄的增长和成人糖尿病，骨折的风险会增加，这种增加不能仅仅用骨矿物质密度（BMD）的变化来解释。新诊断工具和治疗的障碍之一是糖尿病患者和老年人骨折风险不成比例增加的根本原因目前尚不清楚。因此，需要确定与年龄和糖尿病相关的骨骼变化的生物物理基础，这些变化不仅会降低骨强度，还会降低抗骨折能力。针对这一问题，该提案旨在确定晚期糖基化终末产物 (AGE) 的增加是否可以解释糖尿病和衰老对骨抗骨折性（以骨折特性为特征）的影响，并确定 AGE 抑制剂和/或抗氧化剂既可以改善骨结构的质量，又可以增加骨的断裂性能。目标 1 将确定骨结构、BMD 和 AGE 在 2 型糖尿病 (T2D) 和衰老对骨骨折特性的影响中的作用。在第一个实验中，将从 24 周和 32 周龄的 T2D 大鼠和非糖尿病大鼠身上收集骨骼。在第二个实验中，将从 4 个月（幼年）、12 个月（成年）和 24 个月（老年）的老龄大鼠身上采集骨骼。所有骨骼都将接受广泛的分析，以确定 BMD 和 AGE 等成分特性以及惯性矩等结构特性对一组生物力学特性（包括传统的强度测量和新的断裂韧性和疲劳寿命测量）的相对贡献。目标 2 将评估胶原蛋白的外源糖化如何影响骨骼的断裂特性。该目的旨在研究 AGE 在骨细胞外基质内的直接积累是否会降低骨的抗骨折能力，以及 AGE 抑制剂吡哆胺（一种 B6 维生素）是否可以防止这种变化。通过适当的对照，人类皮质骨和啮齿动物骨都将在含有或不含有吡哆胺的糖尿病浓度的葡萄糖中孵育。在量化戊糖素（AGE 的生物标志物）和 BMD 的浓度后，每个样本将接受机械测试。就人骨而言，测试将确定增加 AGE 对骨强度、屈服后能量耗散、疲劳寿命以及裂纹萌生和裂纹扩展韧性的影响。对于啮齿动物骨骼，测试将确定增加 AGE 对疲劳寿命和断裂韧性（抵抗裂纹扩展的能力）的影响。目标 3 将评估吡哆胺和 N-乙酰半胱氨酸通过骨结构、BMD 和 AGE 的变化来提高 T2D 老年大鼠模型中骨骨折抵抗力的功效。在这个翻译目标中，将使用这两种化合物研究氧化应激和 AGE 积累在衰老和糖尿病对骨骼的影响中的作用。从 4 个月大开始，非糖尿病和 T2D 大鼠将饮用水、含有吡哆胺的水或含有 N-乙酰半胱氨酸（一种抗氧化剂）的水。经过 4 个月、8 个月和 14 个月（老化）的治疗后，将采集骨骼进行广泛分析，以确定治疗对骨骼结构、成分和生物力学特性的影响。此外，组织学和细胞培养测定将评估化合物对氧化应激和成骨细胞分化的生物效应。为了实现这些目标，微计算机断层扫描将量化体积 BMD；高效液相色谱法将量化交联浓度和胶原蛋白含量；热重分析将量化胶原蛋白和矿物质的含量以及水含量。统计模型将确定结构和成分特性对骨断裂特性的相对贡献。这将解决针对氧化应激和 AGE 的相关性，以改善退伍军人的骨骼健康并预防骨折。长期目标是确定影响抗骨折重要决定因素的因素，并对骨折风险进行准确的诊断评估。 公共卫生相关性： 骨折的发生率随着年龄和糖尿病的增加而增加，这种现象不能归因于骨矿物质密度（BMD）的降低。越来越多的退伍军人的寿命越来越长，而且许多退伍军人正在患上 2 型糖尿病。因此，骨折的数量将会增加。这是一个相当重要的问题，因为 1) 目前基于 BMD 测量的临床工具不一定能识别出有骨折风险的个体，2) 抗骨折不仅仅是低 BMD 和低骨强度的问题，3) 骨折成本高昂4) 目前针对增加 BMD 的骨质疏松药物可能无法降低糖尿病患者的骨折风险。因此，需要确定影响骨组织质量的新机制。因此，拟议的研究探讨了氧化应激和非酶交联的积累作为降低骨骼抗骨折能力的生物物理变化的潜在因素。