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

摘要 慢性肾脏疾病(CKD)在美国每七个人中就有一个受到影响，并显著增加骨折风险。 虽然慢性肾脏病发生在所有年龄段的患者中，但老年人的患病率最高，近40%的人 65岁以上有某种形式的慢性肾脏病，但慢性肾脏病与衰老的相互作用尚未得到充分研究。以CKD为主 以皮质孔洞的形式影响皮质骨，皮质孔与骨的机械性能和 骨折。在慢性肾脏病和衰老中，骨的力学性能也在组织水平上受到影响。瞄准 皮质孔隙度和材料特性对于降低CKD的骨脆性都是重要的。上一首 皮质孔隙度的研究侧重于防止孔洞的形成，而孔隙度反转的研究 (填充)是缺乏的。我们已经证明，在甲状旁腺激素被有效抑制之后，就会出现毛孔填充。 (PTH)在CKD诱导的皮质多孔性的幼年动物中。因为已知成骨细胞的功能是 随着年龄的增长，填充是否会在老年CKD中受到损害，或者是否有必要 用抗硬化素抗体(Romosozumab)等药物进行的合成代谢药物治疗。此外，它仍然是 无论是幼年动物还是老年动物，在毛孔填充过程中形成的骨骼是否具有足够的质量来 改善骨骼力学性能。因此，这一提议的全局假设是，仅抑制PTH 不足以促进老化骨骼中正常骨基质的皮质毛孔填充，这将需要两个 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。 确定甲状旁腺激素抑制或合成代谢药物治疗的单独效果与它们联合治疗的疗效 促进青年和老年慢性肾脏病患者的皮质毛孔充盈。青年和老年(16周岁和66周岁)男性和 雌性C57BL/6J小鼠将饲喂含腺嘌呤的饲料，以诱导CKD和皮质孔洞。动物们会 然后作为未治疗(对照组)或接受4周的甲状旁腺激素抑制药物治疗(金纳多，饮食中)， 合成代谢药物治疗(Romosozumab)，或两者合用。主要成果将包括高分辨率计算机 断层成像、组织学和基因表达。明确目标2.定义机械和材料 填充的骨骼的特性。来自Aim 1的组织将被评估新形成的组织的机械性能 使用拉曼光谱和纳米压痕测量皮质孔内的骨。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种肥沃的 培训环境，申请人可以在其中扩大对骨骼、衰老和慢性肾脏的了解 现有翻译协作团队中的疾病。艾伦博士(骨骼生物学)的指导团队， 怀特博士(矿物质代谢)、华莱士博士(骨骼力学)和莫博士(肾脏病)已经建立了 导师的跟踪记录，以增加卓越的、广泛的实验室和教学培训机会 IUSM的肾脏病和骨骼生物学。

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.