Post-transcriptional Regulation of Parathyroid Hormone Gene Expression in Health and Disease
Parathyroid hormone (PTH) determines mineral metabolism and bone strength. Changes in serum calcium are sensed by the parathyroid calcium receptor. Secondary hyperparathyroidism (SHP) due to chronic hypocalcemia or chronic kidney disease (CKD) are charact
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Tally Naveh-Many
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Introduction
Parathyroid hormone (PTH) regulates serum calcium and phosphate levels and bone strength. Changes in serum calcium are sensed by the seven trans membrane G-protein coupled calcium sensing receptor (CaR) on the parathyroid cell membrane. The parathyroid is unique in that the trigger for PTH secretion is a low extra-cellular calcium rather than high calcium as for other hormones. Small decreases in serum calcium and more prolonged increases in serum phosphate stimulate the parathyroid to secrete PTH which then acts on its target organs the kidney and bone to correct serum calcium and phosphate levels (Fig. 11.1) (Silver and Naveh-Many 2009). Dietary induced hypocalcemia or uremia lead to secondary hyperparathyroidism (SHP) with increased serum PTH, PTH mRNA levels and parathyroid cell proliferation (Moallem et al. 1998; Naveh-Many et al. 1995). SHP is a common disorder in patients with CKD and is characterized by excessive serum PTH levels, parathyroid hyperplasia and an imbalance in calcium and phosphorus metabolism. SHP develops early in the course of CKD and becomes more prominent as kidney function declines. SHP of CKD is associated with an increased morbidity and mortality (Silver et al. 2002). Parathyroid cells have few secretory granules as compared to other endocrine cells and therefore PTH production is regulated largely at the levels of PTH gene expression and parathyroid cell proliferation (Habener et al. 1984). The changes in PTH gene expression by calcium phosphate and CKD are due to post-transcriptional mechanisms affecting PTH mRNA stability. The parathyroid also responds to changes in serum 1,25(OH)2 vitamin D (1,25D) which decreases PTH levels. PTH
T. Naveh-Many, PhD (*) Minerva Center for Calcium and Bone Metabolism, Department of Nephrology, Hadassah Hospital, Hadassah Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel e-mail: [email protected] © Springer International Publishing Switzerland 2016 K.M.J. Menon, A.C. Goldstrohm (eds.), Post-transcriptional Mechanisms in Endocrine Regulation, DOI 10.1007/978-3-319-25124-0_11
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P
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FGF23
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Fig. 11.1 Calcium, phosphate, PTH, FGF23, 1,25D and FGF23 interactions. There are endocrinological feedback loops that govern mineral homeostasis. FGF23, fibroblast growth factor 23; PTH, parathyroid hormone, P, serum phosphate (Silver and Naveh-Many 2009)
in turn, increases the renal synthesis of 1,25D. 1,25D then increases blood calcium largely by increasing the efficiency of intestinal calcium absorption (Fig. 11.1). The increased serum calcium would shut down PTH secretion by activating the parathyroid calcium sensing receptor (CaR) (Brown et al. 1993). In contrast to the post-transcriptional regulation of PTH gene expression by changes in serum calcium and phosphate levels and CKD, 1,25D decreases PTH gene transcription in vitro and in vivo (Silver et al. 1985, 1986; Russell et al. 1986). The 1,25D receptor (VDR) is expre
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