Effects of Advanced Glycation Endproducts on Type 2 Diabetic and Fragility Fractures

晚期糖基化终产物对 2 型糖尿病和脆性骨折的影响

• 批准号: 10522698
• 负责人: Deepak Vashishth
• 金额: $ 59.88万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522698
• 关键词: Advanced Glycosylation End Products; Affect; Age; Aging; Assessment tool; Biological Assay; Biological Markers; Body Composition; Bone Density; Bone Matrix; Cadaver; Calcium ion; Charge; Clinical; Collagen; Crystallization; Diabetes Mellitus; Diagnosis; Dominant-Negative Mutation; Etiology; Exhibits; Femur; Fracture; Glucose; Glyoxal; Goals; Growth; Health; Health Care Costs; High Fat Diet; Hip Fractures; Human; Hydroxyapatites; Hyperglycemia; Impairment; In Vitro; Insulin-Like-Growth Factor I Receptor; Length; Link; Lipids; MM form creatine kinase; Measures; Mechanics; Minerals; Modification; Molecular; Mus; N(6)-carboxymethyllysine; Natural Products; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Patients; Persons; Post-Translational Protein Processing; Predisposition; Process; Property; Proteins; Quality of life; Reaction; Ribose; Risk; Roentgen Rays; Role; Serum; Skin; Specimen; Techniques; Testing; Time; Tissues; Type 2 diabetic; Urine; base; bone; bone fragility; bone loss; bone quality; bone toughness; cohort; cortical bone; diabetes control; diabetic; fracture risk; fragility fracture; glycation; health data; high risk; in vitro Model; in vivo; long bone; mechanical properties; microCT; mineralization; mouse model; muscle engineering; non-diabetic; oxidation; pentosidine; promoter; skeletal; spine bone structure; substantia spongiosa; sugar; tool

Abstract Bone fractures contribute significantly to healthcare cost affecting the quality of life. Clinically, fracture risk can be predicted by dual x-ray absorptiometry (DXA) or the fracture risk assessment (FRAX) tool. Because type 2 diabetes (T2D) patients exhibit high bone mineral density (BMD), both tools fail to correctly predict fracture risk, leading to a significant increase of fragility fractures in diabetic subjects. Therefore, there is a need to investigate how modifications in collagen and other organic components in bone can predict diabetic fractures. Pentosidine (PEN), a fluorescent Advanced Glycation Endproduct (AGE) that forms in bone by reaction between sugars and proteins, is the only established marker of bone fragility. However, it does not consistently predict T2D and fragility fractures. Here, for the first time in bone, we demonstrate the presence of carboxymethyl-lysine (CML), a non-fluorescent glycoxidative AGE, and present a technique to measure it. We show that it forms in abundance in bone and is highly correlated to loss of bone toughness. We demonstrate that, in contrast to other AGEs, CML is upregulated >60% in T2D human bone compared to their age-matched controls. We then provide evidence that CML promotes formation and growth of additional hydroxyapatite (HA) crystals, similar to human T2D condition, and forms a ‘molecular link’ between the organic and inorganic components of bone (collagen-HA interface) impairing bone quality. Our overall hypothesis is that CML is a ‘new and relevant’ biomarker of T2D fracture that captures the effects of both hyperglycemia and oxidative stress in bone and explains the susceptibility of bone to fracture in T2D. Using an obese and a non-obese mouse model of T2D, that mimic both causality and impact of human T2D on bone, we provide evidence that T2D increases AGEs, with CML explaining bone fragility. Similarly, using data from the Health, Aging and Body Composition (ABC) study we show that higher serum CML levels are associated with increased risk of incident clinical fractures in T2D, independent of BMD. Thus, our overall goal is to establish CML as a new and relevant biomarker of bone fragility and determine how it contributes to bone fragility in T2D. Using in vitro models, ex vivo human cadaveric tissue, in vivo mouse models of obese and non-obese T2D, and existing data from the Health ABC study we will pursue there aims: Aim 1: Establish NEG conditions for enhanced formation of CML over other AGEs and determine the mechanism(s) by which it reduces energy dissipation in bone; Aim 2: Determine the contribution of CML and other AGEs to alterations in bone matrix and energy dissipation in human T2D vertebrae and cortical and cancellous bone from hip fracture patients; and Aim 3: Validate CML as a biomarker of T2D bone fragility and establish its association with hyperglycemia and oxidative stress. Our findings will provide a new understanding of the mechanism and the effects of CML and other AGEs on bone fractures leading to new strategies to predict, manage and mitigate T2D and fragility fractures.

抽象的 骨折对影响生活质量的医疗保健成本产生了重大贡献。在临床上，断裂风险 可以通过双X射线绝对肽（DXA）或断裂风险评估（FRAX）工具来预测。因为 2型糖尿病（T2D）患者暴露了高骨矿物质密度（BMD），这两种工具都无法正确预测 断裂风险，导致糖尿病患者脆弱性骨折的显着增加。因此，有一个 需要研究胶原蛋白和其他有机成分的修饰如何预测 糖尿病性骨折。戊糖苷（PEN），一种形成在形成的荧光高级糖基化末代（年龄） 通过糖和蛋白质之间的反应，骨骼是骨骼脆弱性的唯一已建立的标记。但是，它 不能始终如一地预测T2D和脆弱性骨折。在这里，我们第一次在骨头中演示了 羧甲基赖氨酸（CML）的存在，一种非荧光糖化年龄，并将一种技术呈现给 测量它。我们表明，它在骨骼中的抽象中形成，并且与骨骼韧性的丧失高度相关。 我们证明，与其他年龄相比，CML在T2D人骨中更新> 60％ 到他们年龄匹配的控件。然后，我们提供证据表明CML促进了形成和成长 与人T2D相似的其他羟基磷灰石（HA）晶体，形成了“分子链接” 在骨（胶原-HA界面）的有机和无机成分之间，损害了骨质的质量。我们的 总体假设是CML是T2D骨折的“新的且相关”的生物标志物，可捕获 高血糖和骨骼中的氧化应激的影响，并解释了骨骼的敏感性 T2D中的断裂。使用肥胖的T2D的肥胖和非肥胖小鼠模型，既模仿休闲性和 人类T2D对骨骼的影响，我们提供了T2D增加年龄的证据，CML解释了骨骼 脆弱性。同样，使用来自健康，衰老和身体成分（ABC）研究的数据，我们表明 较高的血清CML水平与T2D中发生临床骨折的风险增加有关， 独立于BMD。这就是我们的总体目标是将CML建立为骨头的新生物标志物 脆弱性并确定其如何促进T2D中的骨骼脆弱性。使用体外模型，离体人 尸体组织，肥胖和非肥胖T2D的体内小鼠模型以及健康的现有数据 ABC研究我们将在此追求目标：目标1：建立否定条件以增强CML的形成 其他年龄并确定减少骨骼能量耗散的机制；目标2： 确定CML和其他年龄对骨基质改变的贡献以及在 髋部骨折患者的人类T2D椎骨以及皮质和抵消骨；和目标3：验证CML 作为T2D骨脆弱性的生物标志物，并建立了与高血糖和氧化应激的关联。 我们的发现将为CML和其他年龄的机制和影响提供新的理解 骨折导致了新的策略来预测，管理和减轻T2D和脆弱性骨折。