Minerva Center for Bone and Mineral Research, Nephrology Services, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
Nursing, Jerusalem College of Technology, Israel.
FEBS J. 2020 Jul;287(14):2903-2913. doi: 10.1111/febs.15300. Epub 2020 Apr 9.
Parathyroid hormone (PTH) regulates serum calcium levels and bone strength. Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that correlates with morbidity and mortality. In experimental SHP, the increased PTH gene expression is due to increased PTH mRNA stability and is mediated by protein-PTH mRNA interactions. Adenosine-uridine-rich binding factor 1 (AUF1) stabilizes and K-homology splicing regulatory protein (KSRP) destabilizes PTH mRNA. The peptidyl-prolyl cis/trans isomerase Pin1 acts on target proteins, including mRNA-binding proteins. Pin1 leads to KSRP dephosphorylation, but in SHP, parathyroid Pin1 activity is decreased and phosphorylated KSRP fails to bind PTH mRNA, leading to increased PTH mRNA stability and levels. A further level of post-transcriptional regulation occurs through microRNA (miRNA). Dicer mediates the final step of miRNA maturation. Parathyroid-specific Dicer knockout mice that lack miRNAs in the parathyroid develop normally. Surprisingly, these mice fail to increase serum PTH in response to both hypocalcemia and CKD, indicating that parathyroid Dicer and miRNAs are essential for stimulation of the parathyroid. Human and rodent parathyroids share similar miRNA profiles that are altered in hyperparathyroidism. The evolutionary conservation of abundant miRNAs and their regulation in hyperparathyroidism indicate their significance in parathyroid physiology and pathophysiology. let-7 and miR-148 antagonism modifies PTH secretion in vivo and in vitro, suggesting roles for specific miRNAs in parathyroid function. This review summarizes the current knowledge on the post-transcriptional mechanisms of PTH gene expression in SHP and the central contribution of miRNAs to the high serum PTH levels of both primary hyperparathyroidism and SHP.
甲状旁腺激素（PTH）调节血清钙水平和骨强度。继发性甲状旁腺功能亢进症（SHP）是慢性肾脏病（CKD）的常见并发症，与发病率和死亡率相关。在实验性 SHP 中，PTH 基因表达的增加是由于 PTH mRNA 稳定性增加，并且由蛋白-PTH mRNA 相互作用介导。腺苷-尿嘧啶丰富结合因子 1（AUF1）稳定 PTH mRNA，而 K-同源结构域剪接调节蛋白（KSRP）使 PTH mRNA 不稳定。肽脯氨酰顺/反式异构酶 Pin1 作用于靶蛋白，包括 mRNA 结合蛋白。Pin1 导致 KSRP 去磷酸化，但在 SHP 中，甲状旁腺 Pin1 活性降低，磷酸化的 KSRP 未能结合 PTH mRNA，导致 PTH mRNA 稳定性和水平增加。转录后调节的进一步水平是通过 microRNA（miRNA）实现的。Dicer 介导 miRNA 成熟的最后一步。缺乏甲状旁腺 miRNA 的甲状旁腺特异性 Dicer 敲除小鼠正常发育。令人惊讶的是，这些小鼠在低钙血症和 CKD 时未能增加血清 PTH，表明甲状旁腺 Dicer 和 miRNAs 对于甲状旁腺的刺激是必不可少的。人类和啮齿动物的甲状旁腺具有相似的 miRNA 谱，在甲状旁腺功能亢进症中发生改变。丰富的 miRNA 在进化上的保守性及其在甲状旁腺功能亢进症中的调节表明它们在甲状旁腺生理学和病理生理学中的重要性。let-7 和 miR-148 拮抗作用在体内和体外改变 PTH 分泌，表明特定 miRNA 在甲状旁腺功能中的作用。本综述总结了 SHP 中 PTH 基因表达的转录后机制以及 miRNA 对原发性甲状旁腺功能亢进症和 SHP 中高血清 PTH 水平的核心贡献的最新知识。
