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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/F795    most recent 90625.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nechama, M. Articles by Naveh-Many, T. Search for Related Content PubMed PubMed Citation Articles by Nechama, M. Articles by Naveh-Many, T.

Regulation of PTH mRNA stability by the calcimimetic R568 and the phosphorus binder lanthanum carbonate in CKD

Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah—Hebrew University Medical Center, Jerusalem, Israel

Submitted 22 October 2008 ; accepted in final form 6 January 2009

Secondary hyperparathyroidism is characterized by increased parathyroid hormone (PTH) mRNA stability that leads to increased PTH mRNA and serum PTH levels. PTH gene expression is reduced by the calcimimetic R568 and the oral phosphorus binder lanthanum carbonate (La). Changes in PTH mRNA stability are regulated by the binding of trans-acting stabilizing and destabilizing factors to a defined cis element in the PTH mRNA 3'-untranslated region (UTR). Adenosine-uridine (AU)-binding factor 1 (AUF1) is a PTH mRNA-stabilizing protein, and K-homology splicing regulatory protein (KSRP) is a destabilizing protein that targets mRNAs, including PTH mRNA, to degradation by the ribonuclease complex exosome. We now show that KSRP-PTH mRNA binding is decreased in parathyroids from rats with adenine-induced chronic kidney disease (CKD) where PTH mRNA is more stable. KSRP-PTH mRNA binding is increased by treatment with both R568 and La, correlating with decreased PTH gene expression. In vitro degradation assays using transcripts for PTH mRNA and rat parathyroid extracts reproduce the differences in mRNA stability in vivo. Accordingly, PTH mRNA is destabilized in vitro by parathyroid extracts from CKD rats treated with R568 or La compared with parathyroid extracts from untreated CKD rats. This destabilizing effect of R568 and La is dependent on KSRP and the PTH mRNA 3'-UTR. Therefore, the calcimimetic R568 and correction of serum phosphorus by La determine PTH mRNA stability through KSRP-mediated recruitment of a degradation complex to the PTH mRNA, thereby decreasing PTH expression.

K-homology splicing regulatory protein; protein-ribonucleic acid interactions; calcium receptor; secondary hyperparathyroidism; parathyroid hormone; chronic kidney disease

This article has been cited by other articles:

				V. Lavi-Moshayoff, J. Silver, and T. Naveh-Many Human PTH gene regulation in vivo using transgenic mice Am J Physiol Renal Physiol, September 1, 2009; 297(3): F713 - F719. [Abstract] [Full Text] [PDF]