The Effect of Etelcalcetide on Bone-tissue Properties in End Stage Kidney Disease

Etelcalcetide 对终末期肾病骨组织特性的影响

• 批准号: 10625512
• 负责人: John Damrath
• 金额: $ 5.27万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625512
• 关键词: Advanced Glycosylation End Products; Affect; Aftercare; Age; American; Animals; Architecture; Biochemical; Biochemistry; Biological Markers; Biomedical Engineering; Biopsy; Bone Density; Bone Diseases; Bone Matrix; Bone Tissue; Calcium; Calcium-Sensing Receptors; Carbonates; Chemical Structure; Chemicals; Chief Cell; Chronic; Chronic Kidney Failure; Clinic; Clinical; Clinical Research; Collagen; Data; Dialysis procedure; Disease; Doctor of Philosophy; End stage renal failure; Femur; General Population; Goals; Hardness; Hip Fractures; Histology; Homeostasis; Hormone secretion; Human; Hyperparathyroidism; Image; Incidence; Kidney; Knowledge; Label; Laboratories; Laboratory Finding; Learning; Length; Maps; Measurement; Measures; Mechanics; Medical; Mentors; Minerals; Modeling; Modulus; Molecular Biology Techniques; Monitor; Morphology; Outcome; Outcome Measure; PTH gene; Parathyroid gland; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physicians; Population; Process; Property; Proteoglycan; Raman Spectrum Analysis; Rattus; Research; Research Design; Role; Running; Sampling; Scientist; Secondary Hyperparathyroidism; Specimen; Techniques; Testing; Tetracyclines; Time; Tissues; Training; Translating; United States; Universities; Vitamin D; analog; bone; bone fragility; bone loss; bone mass; bone quality; bone strength; bone turnover; chemical property; clinically relevant; crosslink; crystallinity; doctoral student; drug action; fracture risk; human disease; human subject; improved; mechanical properties; model organism; mortality; nanoindentation; novel; pre-clinical; pyridinoline; skeletal; skills; therapy design

ABSTRACT Chronic kidney disease (CKD) patients are at an alarming risk of fracture-related mortality. The progression of CKD is marked by abnormal biochemistries including disrupted mineral homeostasis and elevated parathyroid hormone (PTH), or hyperparathyroidism (HPT). Chronic HPT is currently thought to be responsible for the dramatic loss of bone mass and increased fracture risk in CKD patients, and thus patients have PTH levels monitored to determine their fracture risk. Further, these patients are commonly given PTH-lowering drugs including calcimimetics. These drugs act by sensitizing the calcium-sensing receptor in parathyroid chief cells, lowering their PTH secretion. While these drugs have been shown to reduce fracture risk in CKD patients on dialysis, there is little known about their effect on bone mass and quality. Interestingly, CKD patients with normal bone mass and controlled PTH levels remain at an increased fracture risk. Thus, there is a critical gap in our understanding of what skeletal properties dictate bone strength in both the disease process and treatment of CKD bone disorder. Recently, there has been increasing recognition of the role of bone quality in determining overall bone strength. Bone quality refers to a combination of bone architecture, chemical composition of the bone matrix, and the resulting whole bone and tissue-level mechanical properties. To date, however, measures of bone quality in the setting of CKD and calcimimetic treatment have not been spatially matched, or colocalized, in bone samples of known tissue age. Based on the above scientific premise, the goal of this proposal is to test the hypothesis that calcimimetic drugs reduce fracture risk by improving bone quality. Specifically, this study will, in addition to measuring changes in bone architecture, spatially match measures of matrix composition and tissue-level mechanical properties before and after calcimimetic treatment. The first Aim is to determine the effects of calcimimetic treatment on matrix composition and mechanical properties in the Cy/+ rat, a slowly progressive model of CKD. This will be accomplished by running colocalized Raman spectroscopy to determine matrix composition and nanoindentation to determine tissue-level mechanical properties on rat femur sections. Fluorescent labels will be given before and after treatment to identify regions of bone formed at each time point and to control for tissue age. Outcomes will include semi-quantitative measurements of mineral and matrix content, crystallinity, and carbonate content as well as measurements of tissue hardness and stiffness. For the second Aim, a similar study will be accomplished using transiliac crest bone biopsies from CKD patients with severe HPT. Specimens will again be controlled for tissue age and will undergo colocalized Raman spectroscopy and nanoindentation. Data from the above Aims will allow us to generate novel correlations between alterations in bone matrix properties and tissue-level mechanics, helping us begin filling the critical gap in our understanding of CKD bone disease. Additionally, because this study navigates between the laboratory and clinic, it provides an excellent opportunity for a physician-scientist in training.

抽象的 慢性肾病（CKD）患者因骨折而死亡的风险令人震惊。的进展 CKD 的特点是生物化学异常，包括矿物质稳态破坏和甲状旁腺升高 激素（PTH）或甲状旁腺功能亢进症（HPT）。目前认为慢性 HPT 是导致 CKD 患者骨量急剧减少，骨折风险增加，因此患者的 PTH 水平 进行监测以确定他们的骨折风险。此外，这些患者通常会服用降低 PTH 的药物 包括拟钙剂。这些药物通过使甲状旁腺主细胞中的钙敏感受体敏感来起作用， 降低 PTH 分泌。虽然这些药物已被证明可以降低 CKD 患者的骨折风险 透析对骨量和骨质量的影响知之甚少。有趣的是，CKD 患者的正常 骨量和受控的 PTH 水平仍然会增加骨折风险。因此，我们的 了解在疾病过程和治疗中哪些骨骼特性决定骨强度 CKD 骨病。近年来，人们越来越认识到骨质量在决定骨密度方面的作用。 整体骨强度。骨质量是指骨结构、骨化学成分的组合 骨基质，以及由此产生的整个骨和组织水平的机械特性。然而迄今为止，措施 CKD 和拟钙剂治疗中的骨质量在空间上不匹配或共定位， 在已知组织年龄的骨骼样本中。基于上述科学前提，本提案的目标是测试 模拟钙药物通过改善骨质量来降低骨折风险的假设。具体来说，这项研究将， 除了测量骨骼结构的变化外，还可以测量基质成分的空间匹配和 拟钙治疗前后的组织水平机械性能。第一个目标是确定 拟钙剂治疗对 Cy/+ 大鼠基质组成和机械性能的影响，缓慢 CKD 的进展模型。这将通过运行共定位拉曼光谱来确定 基质成分和纳米压痕以确定大鼠股骨切片的组织级机械性能。 治疗前后将进行荧光标记，以识别每个时间点形成的骨区域 并控制组织年龄。结果将包括矿物质和基质的半定量测量 含量、结晶度和碳酸盐含量以及组织硬度和刚度的测量。对于 第二个目标，将使用 CKD 患者的经髂嵴骨活检来完成一项类似的研究 严重的HPT。样本将再次受到组织年龄的控制，并将进行共定位拉曼光谱分析 和纳米压痕。来自上述目标的数据将使我们能够在改变之间生成新的相关性 骨基质特性和组织水平力学，帮助我们开始填补我们理解中的关键空白 CKD 骨病。此外，由于这项研究在实验室和诊所之间进行导航，因此它提供了 对医生兼科学家来说是一次绝佳的培训机会。