Post‐transcriptional mechanisms regulating parathyroid hormone gene expression in secondary hyperparathyroidism

Abstract

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.

Kidney failure alters parathyroid Pin1 phosphorylation and parathyroid hormone mRNA binding proteins leading to secondary hyperparathyroidism

“…The Pin -/- mice also had a 2-fold increase in PTH mRNA and protein content in the parathyroid glands, in agreement with their high serum PTH levels. These results support the central role for Pin1 in determining basal PTH levels in vivo (12, 29).…”

“…Pin1-mediated KSRP Ser181 dephosphorylation favors KSRP-PTH mRNA 3'-UTR binding and thus PTH mRNA decay. In SHP, parathyroid Pin1 isomerase activity is decreased and phosphorylated Ser181 KSRP fails to induce PTH mRNA decay, resulting in increased PTH mRNA and serum levels (12,29,30).…”

Parathyroid Cell Proliferation in Secondary Hyperparathyroidism of Chronic Kidney Disease

“…The increase in PTH gene expression in SHP is regulated by posttranscriptional mechanisms that alter PTH mRNA stability and levels. PTH mRNA stability is mediated by PTH mRNA–protein binding orchestrated by the cis-trans isomerase Pin1 [ 33 , 34 ]. microRNAs (miRNAs) also contribute to the stimulation of the parathyroid in SHP [ 35 ].…”

Molecular Mechanisms of Parathyroid Disorders in Chronic Kidney Disease

“…We found that Pin1 mRNA was 30% higher (p < 0.01) in parathyroid adenomas vs. normal parathyroid tissues. Additional proteins that were related to RNA stability as well as protein synthesis and processing, DNA repair and cell growth were also dysregulated [26]. In another human study of single nucleotide polymorphisms (SNP) in the Pin1 gene promoter, in the Chinese Han population in Northwest China, Pin1 C667T genetic variants were associated with CKD SHP.…”

“…Therefore, increases in PTH gene expression are essential for a continued secretion of PTH. The increased PTH gene expression in experimental SHP induced by either uremia or prolonged hypocalcemia is due to post-transcriptional mechanisms that alter PTH mRNA stability and levels [23][24][25][26].…”