Postâtranscriptional mechanisms regulating parathyroid hormone gene expression in secondary hyperparathyroidism
Open Access
- 19 March 2020
- journal article
- review article
- Published by Wiley in The FEBS Journal
- Vol. 287 (14), 2903-2913
- https://doi.org/10.1111/febs.15300
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 proteinâPTH mRNA interactions. AUF1 (adenosineâuridineârich binding factor 1) stabilizes and KSRP (Kâhomology splicing regulatory protein) destabilizes PTH mRNA. The peptidylâprolyl cis/trans isomerase Pin1 acts on target proteins, including mRNAâbinding 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 postâtranscriptional regulation occurs through miRNA. Dicer mediates the final step of miRNA maturation. Parathyroidâspecific 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. letâ7 and miRâ148 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 postâtranscriptional mechanisms of PTH gene expression in SHP and the central contribution of miRNAs to the high serum PTH levels of both primary and SHP.Keywords
Funding Information
- Israel Science Foundation (642/16)
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