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: 8696807
• 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/8696807
• 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 Targeting; 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; 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.

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。新的诊断工具和治疗方法的一个障碍是，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，这些变化会降低骨折阻力，而不仅仅是骨骼强度。针对这一点，该提案旨在确定晚期糖基化终产物（AGEs）的增加是否解释了糖尿病和衰老对骨抗骨折性的影响（以骨折特性为特征），并确定AGE抑制剂和/或抗氧化剂是否可以改善骨结构的质量并增加骨的骨折特性。目的1将确定骨结构，BMD和AGEs在2型糖尿病（T2 D）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周龄和32周龄的T2 D大鼠和非糖尿病大鼠收集骨骼。在第二个实验中，将从4个月龄（年轻）、12个月龄（成年）和24个月龄（老年）的老龄大鼠中采集骨骼。所有骨骼将进行广泛的分析，以确定组成特性（如BMD和AGEs）和结构特性（如惯性矩）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。目的2探讨外源性胶原糖基化对骨断裂特性的影响。本研究的目的是研究AGEs在骨细胞外基质中的直接积累是否会降低骨的抗骨折性，以及AGEs抑制剂吡哆胺（一种B6维生素）是否可以防止这种变化。在适当的对照下，将人皮质骨和啮齿动物骨在含有和不含吡哆胺的糖尿病浓度葡萄糖中孵育。在定量戊糖苷（AGEs的生物标志物）和BMD的浓度后，将对每个样本进行机械试验。在人骨的情况下，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。对于啮齿类动物的骨骼，测试将确定增加AGE对疲劳寿命和断裂韧性的影响，即抵抗裂纹扩展的能力。目的3将评估吡哆胺和N-乙酰半胱氨酸通过骨结构、BMD和AGEs的变化来增加T2 D衰老大鼠模型中骨的抗骨折性的功效。在这个翻译的目的，氧化应激和AGE积累的作用，在衰老和糖尿病对骨的影响将使用这两种化合物进行研究。从4月龄开始，非糖尿病和T2 D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。治疗4个月、8个月和14个月（老化）后，将采集骨骼进行广泛分析，以确定治疗对骨骼结构、组成和生物力学特性的影响。此外，组织学和细胞培养试验将评估化合物对氧化应激和成骨细胞分化的生物学效应。为了实现这些目标，微型计算机断层扫描将量化体积BMD;高效液相色谱将量化交联和胶原蛋白含量的浓度;热重分析将量化胶原蛋白和矿物质组分以及水含量。统计模型将确定结构和组成特性对骨的断裂特性的相对贡献。这将解决靶向氧化应激和AGEs的相关性，以改善退伍军人的骨骼健康和预防骨折。长期目标是确定影响抗骨折性重要决定因素的因素，并制定准确的骨折风险诊断评估。