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）： 衰老和成人糖尿病的骨骼骨折风险有所增加，这种增加不能完全通过骨矿物质密度（BMD）的变化来解释。新的诊断工具和治疗方法的一个障碍是，目前尚不清楚糖尿病患者和老年人骨折风险不成比例的根本原因。因此，有必要确定骨骼与骨骼相关的年龄和糖尿病相关的生物物理基础，从而降低骨折耐药性，而不仅仅是骨骼强度。在解决此问题时，该提案旨在确定高级糖基化终产物（年龄）的增加是否解释了糖尿病和衰老对骨骼抗骨折性的影响（如裂缝特性所表征），并确定年龄抑制剂和/或抗氧化剂是否可以改善骨骼结构的质量和骨骼的质量。 AIM 1将确定骨结构，BMD和年龄在2型糖尿病（T2D）以及衰老对骨骼骨折特性的影响中的作用。在第一个实验中，将在24周和32周龄从T2D大鼠和非糖尿病大鼠收集骨骼。在第二次实验中，将从4个月（年轻），12个月（成人）和24个月（年龄）时从衰老大鼠中收获骨骼。所有骨骼都将进行广泛的分析，以确定组合物特性（例如BMD）和年龄和结构特性的相对贡献，例如惯性力矩对一组生物力学特性，包括传统的强度测量和分裂韧性和疲劳寿命的新测量。 AIM 2将评估胶原蛋白的外源性糖性如何影响骨骼的骨折特性。这个目的研究了骨外基质内年龄的直接积累是否会降低骨骼的断裂性，以及年龄抑制剂吡啶胺（B6维生素）是否可以保护这种变化。通过适当的对照，将在糖尿病浓度的葡萄糖中孵育人皮质骨和啮齿动物骨，有或不包括吡id胺。量化了戊糖苷的浓度，年龄的生物标志物和BMD的浓度后，每个样品将经过机械测试。对于人骨，测试将确定年龄增加对骨强度，产后能量耗散，疲劳寿命以及裂纹发入和裂纹增长韧性的影响。对于啮齿动物骨骼，测试将确定年龄增加对疲劳寿命和断裂韧性的影响，即抵抗裂纹传播的能力。 AIM 3将通过骨结构，BMD和年龄的变化来评估吡ido胺和N-乙酰半胱氨酸在T2D老化大鼠模型中骨折的功效。在这种翻译目的中，将使用这两种化合物研究氧化应激和年龄积累在衰老和糖尿病作用中的作用。从4个月大开始，非糖尿病和T2D大鼠将喝水，吡啶胺和抗氧化剂N-乙酰囊这氨酸的水或水。 4个月，8个月和14个月（老化）治疗后，将收集骨骼进行广泛的分析，以确定治疗对骨骼结构，组成和生物力学特性的影响。此外，组织学和细胞培养分析将评估化合物对氧化应激和成骨细胞分化的生物学作用。为了实现这些目标，微型层析成像将量化体积BMD。高性能液相色谱法将量化交联和胶原蛋白含量的浓度；热量分析将量化胶原蛋白和矿物质分数以及水含量。统计模型将确定结构和组成特性对骨折特性的相对贡献。这将解决靶向氧化应激和年龄以改善退伍军人骨骼健康并预防骨折的相关性。长期目标是确定影响断裂抗性重要决定因素的因素，并对断裂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而增加，这种现象不能归因于骨矿物质密度降低（BMD）。更多的退伍军人寿命更长，许多退伍军人正在发展2型糖尿病。因此，骨折的数量将增加。这是一个相当重大的问题，因为1）基于BMD测量值的当前临床工具不一定识别出骨折风险的人，2）抗断裂抗性不仅仅是BMD低和低骨强度的问题，3）骨折的修复成本高昂，并且与较高的死亡率相关，并且4）降低了疾病的疾病量可能会减少BMD的影响。因此，有必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联交联的积累，这是生物物理变化的因素，从而降低了骨骼抗断裂的抗性。