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: 10672317
• 负责人: Deepak Vashishth
• 金额: $ 59.34万
• 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/10672317
• 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; 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; bone; bone fragility; bone loss; bone quality; bone toughness; cohort; cortical bone; 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.

摘要