Chronic kidney disease effects on cortical bone porosity and mechanics with age

摘要 慢性肾脏疾病（CKD）影响美国七分之一的人，并显着增加骨折风险。 虽然CKD发生在所有年龄段的患者中，但老年人的患病率最高，近40%的个体 65岁以上患有某种形式的CKD，但CKD和衰老的相互作用研究不足。CKD主要 以皮质孔隙率的形式影响皮质骨，皮质孔隙率与骨机械性能呈负相关， 骨折在CKD和老化中，骨的机械性能也在组织水平上受到损害。靶向 皮质多孔性和材料性质对于降低CKD中的骨脆性都是重要的。先前 对皮质孔隙的研究集中在防止孔隙形成，而对孔隙逆转的研究 （填充）缺乏。我们已经证明，孔填充发生后，有效抑制甲状旁腺激素 (PTH)在患有CKD诱导的皮质多孔性的年轻动物中。因为成骨细胞的功能 随着年龄的增长，不清楚填充是否会影响老年CKD或是否需要 用诸如抗硬化蛋白抗体（romosozumab）的药剂进行合成代谢药物治疗。此外，它仍然 尚不清楚在年轻或年老动物的孔隙填充过程中形成的骨是否具有足够的质量， 改善骨机械性能。因此，该建议的总体假设是，单独抑制PTH 不足以促进老化骨中正常骨基质填充皮质孔， 甲状旁腺激素抑制和合成代谢刺激。这一假设将在两个目标中进行评估：具体目标1。 确定PTH抑制或合成代谢药物治疗与其联合治疗的单独效果， 促进青年和老年CKD的皮质孔填充。年轻和老年（16和66周龄）男性， 雌性C57 BL/6 J小鼠将喂食含有腺嘌呤的饮食以诱导CKD和皮质多孔性。动物将 然后作为未治疗（对照）或接受4周的PTH抑制药物治疗（西那卡塞，饮食中）， 合成代谢药物治疗（romosozumab），或两者组合。主要成果将包括高分辨率计算机 断层扫描成像、组织学和基因表达。具体目标2。定义机械和材料 填充骨的特性。将评估来自目标1的组织的新形成的机械性能 使用拉曼光谱学和纳米压痕术测量皮质孔内的骨。全骨机械 性能将通过多种测试方法进行评估。重要的是，拟议的研究提供了一个肥沃的 培训环境，申请人可以在其中扩展对骨骼，衰老和慢性肾脏的理解 在现有的翻译合作团队中。艾伦博士（骨骼生物学）的指导团队， 博士白色（矿物质代谢）、Wallace博士（骨力学）和莫伊博士（肾脏病学）已建立了 导师的跟踪记录，以增加杰出的，广泛的实验室和教学培训机会， 肾脏学和骨骼生物学

ABSTRACT Chronic kidney disease (CKD) affects one in seven individuals in the US and significantly increases fracture risk. While CKD occurs in patients of all ages, the prevalence is highest in the aged, with nearly 40% of individuals over age 65 having some form of CKD yet the interaction of CKD and aging is understudied. CKD primarily affects cortical bone in the form of cortical porosity, which is inversely related to bone mechanical properties and fracture. In CKD and aging, mechanical properties of bone are also compromised at the tissue level. Targeting both cortical porosity and material properties will be important for reducing bone fragility in CKD. Previous research on cortical porosity has focused on preventing pore formation while research on porosity reversal (infilling) is lacking. We have shown that pore infilling occurs following potent suppression of parathyroid hormone (PTH) in young animals with CKD-induced cortical porosity. Because osteoblast function is known to be compromised with age, it is unclear whether infilling would be compromised in aged CKD or if it would necessitate anabolic drug treatment with an agent such as anti-sclerostin antibody (romosozumab). Further, it remains unknown if the bone that forms during pore infilling, in either young or aged animals, is of sufficient quality to improve bone mechanical properties. Thus, the global hypothesis of this proposal is that PTH suppression alone is insufficient to promote cortical pore infilling with normal bone matrix in aging bone and that it will require both PTH suppression and anabolic stimulation. This hypothesis will be assessed in two Aims: Specific Aim 1. Determine the isolated effect of PTH suppression or anabolic drug therapy compared to their combination for promoting cortical pore infilling in young and aged CKD. Young and aged (16 and 66 weeks of age) male and female C57BL/6J mice will be fed a diet containing adenine to induce CKD and cortical porosity. Animals will then serve as untreated (controls) or receive 4 weeks of PTH-suppression drug treatment (cinacalcet, in diet), anabolic drug treatment (romosozumab), or both combined. Key outcomes will include high-resolution computer tomography imaging, histology, and gene expression. Specific Aim 2. Define the mechanical and material properties of the infilled bone. Tissue from Aim 1 will be assessed for mechanical properties of the newly formed bone within the cortical pores using Raman spectroscopy and nanoindentation. Whole bone mechanical properties will be assessed by multiple testing methods. Importantly, the proposed studies provide a fertile training environment in which the applicant can expand understanding of bone, aging, and chronic kidney disease within an existing translational collaborative team. The mentoring team of Dr. Allen (skeletal biology), Dr. White (mineral metabolism), Dr. Wallace (bone mechanics), and Dr. Moe (nephrology) have an established track record of mentorship to augment the outstanding, broad laboratory and didactic training opportunities in both nephrology and skeletal biology at IUSM.