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 慢性肾脏疾病（CKD）患者患与骨折相关死亡的风险令人震惊。进展 CKD以异常生物化学的标志为标志 激素（PTH）或甲状旁腺功能亢进（HPT）。慢性HPT目前被认为是负责 CKD患者的骨骼质量显着丧失和骨折风险增加，因此患者的PTH水平 受到监测以确定其断裂风险。此外，这些患者通常会接受降低PTH的药物 包括钙仪。这些药物通过使甲状旁腺主要细胞中的钙感应受体敏感，起作用， 降低他们的PTH分泌。尽管这些药物已被证明可降低CKD患者的骨折风险 透析，对它们对骨骼质量和质量的影响鲜为人知。有趣的是，CKD患者正常 骨骼质量和受控的PTH水平仍处于骨折风险的增加。因此，我们的差距很大 了解哪种骨骼特性在疾病过程和治疗中都决定骨骼强度 CKD骨障碍。最近，人们对骨骼质量在确定的作用的认识越来越多 总体骨骼强度。骨骼质量是指骨骼结构的结合，化学成分 骨基质以及由此产生的整个骨和组织水平的机械性能。但是，迄今为止的措施 在CKD和钙化处理的环境中，骨质质量尚未在空间上匹配或共定位 在已知组织年龄的骨样品中。基于上述科学前提，该提案的目的是测试 钙化药物通过改善骨质质量来减少断裂风险的假设。具体而言，这项研究将 除了测量骨骼结构的变化外，在空间上匹配基质组成和 组织级的机械性能在钙化处理前后。第一个目的是确定 钙化处理对CY/+大鼠基质组成和机械性能的影响，缓慢 CKD的渐进模型。这将通过运行共定位的拉曼光谱来确定 基质组成和纳米构成，以确定大鼠股骨切片的组织水平机械性能。 荧光标签将在处理前后给出，以识别每个时间点形成的骨骼区域 并控制组织年龄。结果将包括对矿物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。为了 第二个目的，使用来自CKD患者的跨性别rest骨活检来完成类似的研究 严重的HPT。标本将再次受到组织年龄的控制，并将进行共定位的拉曼光谱 和纳米吸引力。上述目标的数据将使我们能够在更改之间产生新的相关性 在骨基质特性和组织级别的力学中，帮助我们开始填补我们的理解中的关键空白 CKD骨病。此外，由于本研究在实验室和诊所之间导航，因此提供了 对于培训的医师科学家来说，这是一个绝佳的机会。