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Pathogenesis of compromised bone quality and mechanics in chronic kidney disease.

慢性肾脏病中骨质量和力学受损的发病机制。

基本信息

批准号：
9751842
负责人：
Matthew R Allen
金额：
$ 43.13万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-05 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751842
关键词：
Acetylcysteine Advanced Glycosylation End Products American Animals Archives Biochemical Markers Biological Assay Biopsy Blood Bone Marrow Bone Marrow Cells Bone structure Chronic Kidney Failure Clinical Collagen Collagen Type I Data Diagnostic radiologic examination Dialysis patients Diet Discrimination Disease Extracellular Matrix Fracture Gene Expression Generations Geometry Goals High Pressure Liquid Chromatography Human Impairment In Vitro Individual Intestinal Absorption Kidney Diseases Measures Mechanics Mesenchymal Stem Cells Modeling Morphology Osteoblasts Outcome Pathogenesis Patients Peripheral Pharmacotherapy Play Positioning Attribute Production Property Proteins Rattus Recording of previous events Regression Analysis Resolution Rodent Role Serum Severity of illness Signal Pathway Small Interfering RNA Specimen Testing Time Tissues Translating Universities Vertebral column Work X-Ray Computed Tomography absorption aged base bone bone age bone imaging bone quality cohort cortical bone crosslink density experimental study fracture risk high risk improved in vivo mechanical properties microCT mineralization morphometry negative affect non-diabetic novel novel strategies osteoblast differentiation pre-clinical receptor expression receptor for advanced glycation endproducts sevelamer skeletal skeletal disorder substantia spongiosa

项目摘要

Reduced bone quality is a key determinant of skeletal fragility in CKD, but the details of this effect are not well defined. Non-enzymatic collagen crosslinks (formed via advanced glycation end-products, AGEs) negatively affect bone mechanical properties and AGEs are elevated in the blood and bone of patients and animals with advanced CKD. We propose that skeletal accumulation of AGE collagen cross links may play a critical role in CKD skeletal fragility and reducing AGEs may represent a novel approach to reduce fracture risk in CKD patients. The overall goal of this study is to test the hypothesis that skeletal AGEs induce negative mechanical and cellular effects in CKD and that circulating AGE levels can help in CKD patient fracture discrimination. This goal will be accomplished through a combination of pre-clinical experiments using our established model of progressive CKD (the Cy/+ rat), novel human biopsy assays, and state-of-the art bone imaging with second generation high resolution peripheral quantitative computed tomography. The multi-university interdisciplinary team is perfectly positioned to undertake this translational work based on their clinical and preclinical expertise in bone, collagen/AGEs, mechanics, and CKD. In Aim 1 we will determine if AGE- lowering drug treatments that reduce endogenous AGE production or gastrointestinal absorption improve the skeletal properties of animals with progressive CKD. In Aim 2 we will assess the effect of disease severity on human bone AGE accumulation and its relationship to mechanical properties by measuring bone AGE levels and mechanical properties from transiliac crest bone biopsies from patients with CKD. In Aim 3, we will quantify the ability of AGE levels to improve fracture discrimination in CKD patients. In Aim 4, we will determine if AGE accumulation in the bone extracellular matrix impairs bone marrow derived osteoblast differentiation, function and AGE receptor expression. The current proposal will build on our body of work characterizing abnormal bone quality in patients with CKD by studying how agents that modulate AGEs through different mechanisms alter skeletal accumulation of AGEs and bone mechanical properties in animals and humans. If these studies show efficacy in benefiting skeletal mechanical properties, these treatments could be rapidly translated into the clinical setting.

骨质量下降是 CKD 骨骼脆性的关键决定因素，但具体细节效果没有明确定义。非酶胶原交联（通过高级糖化形成最终产物 AGE）会对骨机械性能产生负面影响，并且 AGE 会升高患有晚期 CKD 的患者和动物的血液和骨骼。我们建议骨骼 AGE 胶原交联的积累可能在 CKD 骨骼脆性和减少 AGE 可能是降低 CKD 患者骨折风险的一种新方法。这本研究的总体目标是检验骨骼 AGEs 诱导负性的假设 CKD 中的机械和细胞效应以及循环 AGE 水平对 CKD 患者有帮助骨折歧视。这一目标将通过临床前的结合来实现使用我们建立的进行性 CKD 模型（Cy/+ 大鼠）进行实验，新型人类活检分析和第二代高分辨率的最先进的骨成像外周定量计算机断层扫描。多所大学跨学科团队是完全有能力根据他们的临床和临床前情况开展这项转化工作骨骼、胶原蛋白/AGE、力学和 CKD 方面的专业知识。在目标 1 中，我们将确定 AGE- 减少可减少内源性 AGE 产生或胃肠道吸收的药物治疗改善患有进行性 CKD 的动物的骨骼特性。在目标 2 中，我们将评估疾病严重程度对人骨AGE积累的影响及其与力学的关系通过测量骨 AGE 水平和髂嵴骨的机械特性来测量特性 CKD 患者的活组织检查。在目标 3 中，我们将量化 AGE 水平改善的能力 CKD 患者骨折歧视。在目标 4 中，我们将确定 AGE 是否积累在骨细胞外基质损害骨髓源性成骨细胞的分化、功能和 AGE 受体表达。当前的提案将建立在我们的工作基础上通过研究调节 AGE 的药物如何治疗 CKD 患者的骨质量异常通过不同的机制改变骨骼中 AGEs 的积累和骨力学动物和人类的特性。如果这些研究显示对骨骼有益的功效机械特性，这些治疗方法可以快速转化为临床环境。