Elevations in Cortical Porosity Occur Prior to Significant Rise in Serum Parathyroid Hormone in Young Female Mice with Adenine-Induced CKD
Elevations in Cortical Porosity Occur Prior to Significant Rise in Serum Parathyroid Hormone in Young Female Mice with Adenine-Induced CKD
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DOI：
10.1007/s00223-019-00642-w
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发表时间：
2020-04-01
影响因子：
4.2
通讯作者：
Allen, Matthew R.
中科院分区：
文献类型：
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作者：
Metzger, Corinne E.;Swallow, Elizabeth A.;Allen, Matthew R.
慢性肾脏疾病（CKD）主要通过皮质多孔性的发展导致显著的骨丢失。在CKD患者和动物模型中，血清甲状旁腺激素（PTH）的持续升高与皮质多孔性相关。在这项研究中，我们的目的是跟踪皮质孔隙率的进展，并增加PTH利用腺嘌呤诱导的CKD模型。给予年轻雌性小鼠（8周）0.2%腺嘌呤以诱导CKD。在2周、6周和10周后，从腺嘌呤组和年龄匹配的对照组小鼠收集组织。腺嘌呤小鼠血清尿素氮在所有时间点均升高，但血清PTH仅在10周时间点有统计学升高。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，10周腺嘌呤小鼠的皮质孔隙率高14倍。此外，腺嘌呤喂养小鼠的骨细胞核因子κ B配体受体激活因子（RANKL）升高，而腺嘌呤喂养小鼠的骨细胞膜联蛋白V（细胞凋亡的早期标志物）轻度降低。基于这些结果，我们假设高血清甲状旁腺激素信号传递给骨细胞，延长其寿命，导致持续的RANKL，从而驱动皮质中的破骨细胞骨吸收。总之，我们的数据显示腺嘌呤诱导的CKD小鼠血清PTH和皮质孔隙率呈时间依赖性升高，并证明骨细胞RANKL和细胞凋亡的变化可能有助于皮质孔隙的发育。
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 kappa B 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.