Abstract

Chronic kidney disease (CKD) leads to significant bone loss primarily through the development of cortical porosity. In both patients and animal models of CKD, sustained elevations in serum parathyroid hormone (PTH) are associated with cortical porosity. In this study, we aimed to track the progression of cortical porosity and increased PTH utilizing the adenine-induced CKD model. Young female mice (8 weeks) were given 0.2% adenine to induce CKD. Tissues were collected from groups of adenine and age-matched control mice after 2, 6, and 10 weeks. Serum blood urea nitrogen was elevated at all time points in adenine mice, but serum PTH was only statistically elevated at the 10-week time point. Cortical porosity was sevenfold higher in 6-week adenine mice compared to age-matched controls and 14-fold higher in 10-week adenine mice vs. controls. Additionally, osteocyte receptor activator of nuclear factor κB ligand (RANKL) was elevated in adenine-fed mice, while annexin V, an early marker of cellular apoptosis, was mildly decreased in osteocytes in adenine-fed mice. Based on these results, we hypothesize high serum PTH signals to osteocytes prolonging their lifespan resulting in sustained RANKL which drives osteoclastic bone resorption in the cortex. In conclusion, our data show time-dependent elevations in serum PTH and cortical porosity in adenine-induced CKD mice and demonstrate changes in osteocyte RANKL and apoptosis which may contribute to the development of cortical pores.

中文翻译：

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腺嘌呤诱导的CKD的年轻雌性小鼠血清甲状旁腺激素显着升高之前，皮质孔隙率升高。

摘要

慢性肾脏病（CKD）主要通过皮质孔隙的发展导致严重的骨质流失。在CKD的患者和动物模型中，血清甲状旁腺激素（PTH）持续升高与皮质孔隙度有关。在这项研究中，我们旨在利用腺嘌呤诱导的CKD模型追踪皮质孔隙的进展和PTH的增加。雌性幼鼠（8周）接受0.2％腺嘌呤诱导CKD。在第2、6和10周后，从腺嘌呤和年龄匹配的对照组小鼠中收集组织。腺嘌呤小鼠的所有时间点血清尿素氮均升高，但血清PTH仅在10周时间点统计上升高。与年龄匹配的对照组相比，6周腺嘌呤小鼠的皮质孔隙率高7倍，而10周腺嘌呤小鼠的皮质孔隙率则比对照组高14倍。此外，在腺嘌呤喂养的小鼠中，核因子κB配体的骨细胞受体激活剂（RANKL）升高，而在腺嘌呤喂养的小鼠中，细胞凋亡的早期标志物Annexin V在骨细胞中轻度降低。基于这些结果，我们假设高血清PTH信号可延长骨细胞的寿命，从而导致持续的RANKL，从而驱动皮质中破骨细胞的骨吸收。总之，我们的数据显示了腺嘌呤诱发的CKD小鼠血清PTH和皮质孔隙率的时间依赖性升高，并证明了骨细胞RANKL和凋亡的变化，这可能有助于皮质孔的形成。腺嘌呤喂养的小鼠的骨细胞中的Caspase-Aβ轻度降低。基于这些结果，我们假设高血清PTH信号可延长骨细胞的寿命，从而导致持续的RANKL，从而驱动皮质中破骨细胞的骨吸收。总之，我们的数据显示了腺嘌呤诱发的CKD小鼠血清PTH和皮质孔隙率的时间依赖性升高，并证明了骨细胞RANKL和凋亡的变化，这可能有助于皮质孔的形成。腺嘌呤喂养的小鼠的骨细胞中的Caspase-Aβ轻度降低。基于这些结果，我们假设高血清PTH信号可延长骨细胞的寿命，从而导致持续的RANKL，从而驱动皮质中破骨细胞的骨吸收。总之，我们的数据显示了腺嘌呤诱发的CKD小鼠血清PTH和皮质孔隙率的时间依赖性升高，并证明了骨细胞RANKL和凋亡的变化，这可能有助于皮质孔的形成。