Publications by authors named "Tally Naveh-Many"

42 Publications

A molecular circadian clock operates in the parathyroid gland and is disturbed in chronic kidney disease associated bone and mineral disorder.

Kidney Int 2020 12 25;98(6):1461-1475. Epub 2020 Jul 25.

Nephrological Department, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; Nephrological Department, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Circadian rhythms in metabolism, hormone secretion, cell cycle and locomotor activity are regulated by a molecular circadian clock with the master clock in the suprachiasmatic nucleus of the central nervous system. However, an internal clock is also expressed in several peripheral tissues. Although about 10% of all genes are regulated by clock machinery an internal molecular circadian clock in the parathyroid glands has not previously been investigated. Parathyroid hormone secretion exhibits a diurnal variation and parathyroid hormone gene promoter contains an E-box like element, a known target of circadian clock proteins. Therefore, we examined whether an internal molecular circadian clock is operating in parathyroid glands, whether it is entrained by feeding and how it responds to chronic kidney disease. As uremia is associated with extreme parathyroid growth and since disturbed circadian rhythm is related to abnormal growth, we examined the expression of parathyroid clock and clock-regulated cell cycle genes in parathyroid glands of normal and uremic rats. Circadian clock genes were found to be rhythmically expressed in normal parathyroid glands and this clock was minimally entrained by feeding. Diurnal regulation of parathyroid glands was next examined. Significant rhythmicity of fibroblast-growth-factor-receptor-1, MafB and Gata3 was found. In uremic rats, deregulation of circadian clock genes and the cell cycle regulators, Cyclin D1, c-Myc, Wee1 and p27, which are influenced by the circadian clock, was found in parathyroid glands as well as the aorta. Thus, a circadian clock operates in parathyroid glands and this clock and downstream cell cycle regulators are disturbed in uremia and may contribute to dysregulated parathyroid proliferation in secondary hyperparathyroidism.
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http://dx.doi.org/10.1016/j.kint.2020.06.034DOI Listing
December 2020

Parathyroid Cell Proliferation in Secondary Hyperparathyroidism of Chronic Kidney Disease.

Int J Mol Sci 2020 Jun 18;21(12). Epub 2020 Jun 18.

The Wohl Institute for Translational Medicine, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.

Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that correlates with morbidity and mortality in uremic patients. It is characterized by high serum parathyroid hormone (PTH) levels and impaired bone and mineral metabolism. The main mechanisms underlying SHP are increased PTH biosynthesis and secretion as well as increased glandular mass. The mechanisms leading to parathyroid cell proliferation in SHP are not fully understood. Reduced expressions of the receptors for calcium and vitamin D contribute to the disinhibition of parathyroid cell proliferation. Activation of transforming growth factor-α-epidermal growth factor receptor (TGF-α-EGFR), nuclear factor kappa B (NF-kB), and cyclooxygenase 2- prostaglandin E2 (Cox2-PGE2) signaling all correlate with parathyroid cell proliferation, underlining their roles in the development of SHP. In addition, the mammalian target of rapamycin (mTOR) pathway is activated in parathyroid glands of experimental SHP rats. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. Mice with parathyroid-specific deletion of all miRNAs have a muted increase in serum PTH and fail to increase parathyroid cell proliferation when challenged by CKD, suggesting that miRNA is also necessary for the development of SHP. This review summarizes the current knowledge on the mechanisms of parathyroid cell proliferation in SHP.
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http://dx.doi.org/10.3390/ijms21124332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352987PMC
June 2020

Post-transcriptional mechanisms regulating parathyroid hormone gene expression in secondary hyperparathyroidism.

FEBS J 2020 Jul 9;287(14):2903-2913. Epub 2020 Apr 9.

Minerva Center for Bone and Mineral Research, Nephrology Services, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.

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.
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http://dx.doi.org/10.1111/febs.15300DOI Listing
July 2020

Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease.

Kidney Int 2018 08 31;94(2):315-325. Epub 2018 May 31.

Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Electronic address:

The high serum fibroblast growth factor 23 (FGF23) levels in patients with acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with increased morbidity and mortality. Mice with folic acid-induced AKI had an increase in bone FGF23 mRNA expression together with an increase in serum FGF23 and several circulating cytokines including interleukin-6 (IL-6). Dexamethasone partially prevented the increase in IL-6 and FGF23 in the AKI mice. IL-6 knock-out mice fed an adenine diet to induce CKD failed to increase bone FGF23 mRNA and had a muted increase in serum FGF23 levels, compared with the increases in wild-type mice with CKD. Therefore, IL-6 contributes to the increase in FGF23 observed in CKD. Hydrodynamic tail injection of IL-6/soluble IL-6 receptor (sIL-6R) fusion protein hyper IL-6 (HIL-6) plasmid increased serum FGF23 levels. Circulating sIL-6R levels were increased in both CKD and AKI mice, suggesting that IL-6 increases FGF23 through sIL-6R-mediated trans-signaling. Renal IL-6 mRNA expression was increased in mice with either AKI or CKD, suggesting the kidney is the source for the increased serum IL-6 levels in the uremic state. HIL-6 also increased FGF23 mRNA in calvaria organ cultures and osteoblast-like UMR106 cells in culture, demonstrating a direct effect of IL-6 on FGF23 expression. HIL-6 increased FGF23 promoter activity through STAT3 phosphorylation and its evolutionarily conserved element in the FGF23 promoter. Thus, IL-6 increases FGF23 transcription and contributes to the high levels of serum FGF23 in both acute and chronic kidney disease.
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http://dx.doi.org/10.1016/j.kint.2018.02.026DOI Listing
August 2018

Transcription factors that determine parathyroid development power PTH expression.

Kidney Int 2018 01;93(1):7-9

Hadassah Hebrew University Medical Center, Jerusalem, Ein Karem, Israel.

Studies in patients with hypoparathyroidism and knockout mouse models have revealed key transcriptional cascades central for parathyroid organogenesis. Among the transcription factors essential for parathyroid development, Gata3, GCM2, and MafB, are expressed in the developing parathyroids as well as postnatally, implying that they also regulate parathyroid-specific gene expression and function in the adult. PTH gene expression is determined by transcriptional and posttranscriptional mechanisms. The study by Morito et al. demonstrates that MafB contributes to the stimulation of the parathyroid by hypocalcemia and uremia.
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http://dx.doi.org/10.1016/j.kint.2017.08.026DOI Listing
January 2018

and Regulate Parathyroid Hormone Levels in Secondary Hyperparathyroidism.

J Am Soc Nephrol 2017 Aug 15;28(8):2353-2363. Epub 2017 Mar 15.

Nephrology and Hypertension, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and

Secondary hyperparathyroidism commonly complicates CKD and associates with morbidity and mortality. We profiled microRNA (miRNA) in parathyroid glands from experimental hyperparathyroidism models and patients receiving dialysis and studied the function of specific miRNAs. miRNA deep-sequencing showed that human and rodent parathyroids share similar profiles. Parathyroids from uremic and normal rats segregated on the basis of their miRNA expression profiles, and a similar finding was observed in humans. We identified parathyroid miRNAs that were dysregulated in experimental hyperparathyroidism, including miR-29, miR-21, miR-148, miR-30, and miR-141 (upregulated); and miR-10, miR-125, and miR-25 (downregulated). Inhibition of the abundant let-7 family increased parathyroid hormone (PTH) secretion in normal and uremic rats, as well as in mouse parathyroid organ cultures. Conversely, inhibition of the upregulated miR-148 family prevented the increase in serum PTH level in uremic rats and decreased levels of secreted PTH in parathyroid cultures. The evolutionary conservation of abundant miRNAs in normal parathyroid glands and the regulation of these miRNAs in secondary hyperparathyroidism indicates their importance for parathyroid function and the development of hyperparathyroidism. Specifically, let-7 and miR-148 antagonism modified PTH secretion and , implying roles for these specific miRNAs. These findings may be utilized for therapeutic interventions aimed at altering PTH expression in diseases such as osteoporosis and secondary hyperparathyroidism.
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http://dx.doi.org/10.1681/ASN.2016050585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533223PMC
August 2017

The Pas de Trois of Vitamin D, FGF23, and PTH.

J Am Soc Nephrol 2017 02 2;28(2):393-395. Epub 2016 Nov 2.

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

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http://dx.doi.org/10.1681/ASN.2016090944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5280031PMC
February 2017

Micro-RNAs in the parathyroid: a new portal in understanding secondary hyperparathyroidism.

Curr Opin Nephrol Hypertens 2016 07;25(4):271-7

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

Purpose Of Review: Micro-RNAs (miRNAs) are important to the function of many cells including endocrine systems. We present the reported changes in miRNA profiles in parathyroid adenomas and carcinomas. We review the essential roles of parathyroid miRNAs to the response of the parathyroid to hypocalcemia and uremia.

Recent Findings: miRNA profiling in parathyroid adenomas and carcinomas revealed alterations in their miRNA expression. To study the function of miRNAs in the parathyroid, mice with parathyroid-specific deletion of dicer, the enzyme essential for miRNA maturation, were studied. Remarkably, the parathyroid-Dicer mice failed to increase serum parathyroid hormone (PTH) after acute hypocalcemia and in parathyroid organ cultures. Moreover, the parathyroid-Dicer mice had an impaired increase in serum PTH, PTH mRNA and parathyroid cell proliferation after both chronic hypocalcemia and uremia. In contrast, the response of the parathyroid- Dicer mice to hypercalcemia and a calcimimetic was intact.

Summary: The stimulation of the parathyroid by hypocalcemia and uremia is miRNA dependent, as opposed to suppression of the parathyroid by hypercalcemia or a calcimimetic that is miRNA independent. miRNAs are essential for the generation of experimental secondary hyperparathyroidism and may be novel targets for its management in chronic kidney disease patients.
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http://dx.doi.org/10.1097/MNH.0000000000000227DOI Listing
July 2016

The fibroblast growth factor receptor mediates the increased FGF23 expression in acute and chronic uremia.

Am J Physiol Renal Physiol 2016 Feb 26;310(3):F217-21. Epub 2015 Aug 26.

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

Serum FGF23 is markedly elevated in chronic kidney disease and has been associated with poor long-term outcomes. FGF23 expression is increased by activation of the FGF receptor 1 (FGFR1) in rats with normal renal function and in vitro in bone-derived osteoblast-like cells. We studied the regulation of FGF23 by FGFR1 in vivo in acute and chronic uremia in mice and rats. Folic acid-induced acute kidney injury increased calvaria FGF23 mRNA and serum FGF23 and parathyroid hormone (PTH) levels at 6 h. The FGFR1 receptor inhibitor PD173074 prevented the folic acid-induced increase in both FGF23 mRNA and serum levels but had no effect on serum PTH levels. A more prolonged uremia due to an adenine high-phosphorus diet for 14 days resulted in high levels of FGF23 mRNA and serum FGF23 and PTH. PD173074 decreased serum FGF23 and mRNA levels with no effect on PTH in the adenine high phosphorus-induced uremic rats. Therefore, a derangement in FGF23 regulation starts early in the course of acute kidney injury, is in part independent of the increase in serum PTH, and involves activation of FGFR1. It is possible that FGFR1 in the osteocyte is activated by locally produced canonical FGFs, which are increased in uremia. This is the first demonstration that activation of FGFR1 is essential for the high levels of FGF23 in acute and chronic experimental uremia.
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http://dx.doi.org/10.1152/ajprenal.00332.2015DOI Listing
February 2016

Phosphorylation of Ribosomal Protein S6 Mediates Mammalian Target of Rapamycin Complex 1-Induced Parathyroid Cell Proliferation in Secondary Hyperparathyroidism.

J Am Soc Nephrol 2016 Apr 17;27(4):1091-101. Epub 2015 Aug 17.

Department of Nephrology, Hadassah-Hebrew University Medical Center, and

Secondary hyperparathyroidism is characterized by increased serum parathyroid hormone (PTH) level and parathyroid cell proliferation. However, the molecular pathways mediating the increased parathyroid cell proliferation remain undefined. Here, we found that the mTOR pathway was activated in the parathyroid of rats with secondary hyperparathyroidism induced by either chronic hypocalcemia or uremia, which was measured by increased phosphorylation of ribosomal protein S6 (rpS6), a downstream target of the mTOR pathway. This activation correlated with increased parathyroid cell proliferation. Inhibition of mTOR complex 1 by rapamycin decreased or prevented parathyroid cell proliferation in secondary hyperparathyroidism rats and in vitro in uremic rat parathyroid glands in organ culture. Knockin rpS6(p-/-) mice, in which rpS6 cannot be phosphorylated because of substitution of all five phosphorylatable serines with alanines, had impaired PTH secretion after experimental uremia- or folic acid-induced AKI. Uremic rpS6(p-/-) mice had no increase in parathyroid cell proliferation compared with a marked increase in uremic wild-type mice. These results underscore the importance of mTOR activation and rpS6 phosphorylation for the pathogenesis of secondary hyperparathyroidism and indicate that mTORC1 is a significant regulator of parathyroid cell proliferation through rpS6.
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http://dx.doi.org/10.1681/ASN.2015040339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814192PMC
April 2016

Parathyroid-specific deletion of dicer-dependent microRNAs abrogates the response of the parathyroid to acute and chronic hypocalcemia and uremia.

FASEB J 2015 Sep 8;29(9):3964-76. Epub 2015 Jun 8.

*Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel; and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

MicroRNAs (miRNAs) down-regulate gene expression and have vital roles in biology but their functions in the parathyroid are unexplored. To study this, we generated parathyroid-specific Dicer1 knockout (PT-Dicer(-/-) ) mice where parathyroid miRNA maturation is blocked. Remarkably, the PT-Dicer(-/-) mice did not increase serum parathyroid hormone (PTH) in response to acute hypocalcemia compared with the >5-fold increase in controls. PT-Dicer(-/-) glands cultured in low-calcium medium secreted 5-fold less PTH at 1.5 h than controls. Chronic hypocalcemia increased serum PTH >4-fold less in PT-Dicer(-/-) mice compared with control mice with no increase in PTH mRNA levels and parathyroid cell proliferation compared with the 2- to 3-fold increase in hypocalcemic controls. Moreover, uremic PT-Dicer(-/-) mice increased serum PTH and FGF23 significantly less than uremic controls. Therefore, stimulation of the parathyroid by both hypocalcemia and uremia is dependent upon intact dicer function and miRNAs. In contrast, the PT-Dicer(-/-) mice responded normally to activation of the parathyroid calcium-sensing receptor (Casr) by both hypercalcemia and a calcimimetic that decreases PTH secretion, demonstrating that they are dicer-independent. Therefore, miRNAs are essential for the response of the parathyroid to both acute and chronic hypocalcemia and uremia, the major stimuli for PTH secretion.
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http://dx.doi.org/10.1096/fj.15-274191DOI Listing
September 2015

Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription.

Kidney Int 2014 Dec 18;86(6):1106-15. Epub 2014 Jun 18.

Department of Nephrology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Parathyroid hormone (PTH) increases FGF23 mRNA and protein levels in vivo and in vitro. Here we tested whether the increased FGF23 expression by PTH is mediated by the orphan nuclear receptor Nurr1. PTH increased Nurr1 mRNA levels prior to elevation of FGF23 mRNA levels in UMR-106 rat osteoblast-like cells. Activation of PKA increased both FGF23 and Nurr1 mRNA levels. Modification of Nurr1 expression showed that Nurr1 is essential for the PTH-mediated increase in FGF23 and luciferase reporter gene experiments identified a functional promoter region containing several potential Nurr1 binding sites. Chromatin immunoprecipitation assays confirmed the binding of Nurr1 to these regions in the FGF23 promoter. In vivo, Nurr1 mRNA and protein levels were increased in calvaria from rats with experimental CKD together with high PTH and FGF23 expression. Calcimimetics decrease PTH and FGF23 levels in CKD patients. Importantly, in rats with experimental CKD, the calcimimetic R568 decreased PTH expression, calvaria Nurr1 mRNA and protein levels, and FGF23 mRNA. Immunohistochemistry for Nurr1 showed an increase in the number of Nurr1 expressing osteocytes in the femurs of rats with CKD and this was decreased by R568. Thus, the effect of PTH to increase FGF23 transcription is mediated by Nurr1 in vitro and in vivo. In CKD, calcimimetics decrease PTH, which in turn decreases Nurr1 and consequently FGF23.
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http://dx.doi.org/10.1038/ki.2014.215DOI Listing
December 2014

FGF-23 and secondary hyperparathyroidism in chronic kidney disease.

Nat Rev Nephrol 2013 Nov 23;9(11):641-9. Epub 2013 Jul 23.

Hadassah Hebrew University Medical Center, Minerva Center for Calcium and Bone Metabolism, Nephrology, Ein Karem, Jerusalem 91120, Israel.

The metabolic changes that occur in patients with chronic kidney disease (CKD) have a profound influence on mineral and bone metabolism. CKD results in altered levels of serum phosphate, vitamin D, calcium, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23); the increased levels of serum phosphate, PTH and FGF-23 contribute to the increased cardiovascular mortality in affected patients. FGF-23 is produced by osteocytes and osteoblasts and acts physiologically in the kidney to induce phosphaturia and inhibit the synthesis of 1,25-dihydroxyvitamin D3. PTH acts directly on osteocytes to increase FGF-23 expression. In addition, the high levels of PTH associated with CKD contribute to changes in bone remodelling that result in decreased levels of dentin matrix protein 1 and the release of low-molecular-weight fibroblast growth factors from the bone matrix, which stimulate FGF-23 transcription. A prolonged oral phosphorus load increases FGF-23 expression by a mechanism that includes local changes in the ratio of inorganic phosphate to pyrophosphate in bone. Other factors such as dietary vitamin D compounds, calcium, and metabolic acidosis all increase FGF-23 levels. This Review discusses the mechanisms by which secondary hyperparathyroidism associated with CKD stimulates bone cells to overexpress FGF-23 levels.
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http://dx.doi.org/10.1038/nrneph.2013.147DOI Listing
November 2013

FGF23 and the parathyroid.

Adv Exp Med Biol 2012 ;728:92-9

Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Klotho and fibroblast growth factor 1 (FGFR1) are expressed not only in FGF23's classical target organ, the kidney, but also in other organs such as the parathyroid. FGF23 acts on the parathyroid to decrease PTH mRNA and serum PTH levels. It does this by activating the MAPK pathway. In chronic kidney disease there are very high levels of serum FGF23 together with increased serum PTH levels, implying resistance of the parathyroid to the action of FGF23. This has been shown in parathyroid tissue surgically removed from dialysis patients as well as in experimental models of uremia to be due to down-regulation of klotho-FGFR1 expression in the parathyroid. Moreover, the parathyroids of rats with advanced uremia do not respond to administered FGF23 by activation of the MAPK pathway or inhibition of PTH secretion. Therefore, there is down-regulation of parathyroid klotho-FGFR1 in CKD which correlates with the resistance of the parathyroid to FGF23. A further subject of great interest in this field is the effect of PTH to directly increase FGF23 expression by osteoblast like cells in culture and the observations that parathyroidectomy prevents and corrects the increased serum FGF23 level of experimental CKD as well as decreases FGF23 in patients with CKD. There is therefore a negative feedback loop between bone and the parathyroid.
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http://dx.doi.org/10.1007/978-1-4614-0887-1_6DOI Listing
April 2012

PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop.

Am J Physiol Renal Physiol 2010 Oct 4;299(4):F882-9. Epub 2010 Aug 4.

Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew Univ. Medical Center, PO Box 12000, Jerusalem, Israel 91120.

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) target the kidney to cause a phosphaturia. FGF23 also acts on the parathyroid to decrease PTH expression, but in chronic kidney disease (CKD) there are high-serum PTH and FGF23 levels and resistance of the parathyroid to FGF23. We now report that PTH acts on bone to increase FGF23 expression and characterize the signal transduction pathway whereby PTH increases FGF23 expression. Remarkably, we show that PTH is necessary for the high-FGF23 levels of early kidney failure due to an adenine high-phosphorus diet. Parathyroidectomy before the diet totally prevented the fivefold increase in FGF23 levels in kidney failure rats. Moreover, parathyroidectomy of early kidney failure rats corrected their high-FGF23 levels. Therefore, in early kidney failure, the high-FGF23 levels are dependent on the high-PTH levels. PTH infusion for 3 days to mice with normal renal function increased serum FGF23 and calvaria FGF23 mRNA levels. To demonstrate a direct effect of PTH on FGF23, we added PTH to rat osteoblast-like UMR106 cells. PTH increased FGF23 mRNA levels (4-fold) and this effect was mimicked by a PKA activator, forskolin. PTH also decreased SOST mRNA levels (3-fold). SOST codes for sclerostin, a Wnt pathway inhibitor, which is a PTH receptor (PTH1R) target. The effect of PTH was prevented by added sclerostin. Therefore, PTH increases FGF23 expression which involves the PKA and Wnt pathways. The effect of PTH on FGF23 completes a bone-parathyroid endocrine feedback loop. Importantly, secondary hyperparathyroidism is essential for the high-FGF23 levels in early CKD.
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http://dx.doi.org/10.1152/ajprenal.00360.2010DOI Listing
October 2010

FGF23 and the parathyroid glands.

Pediatr Nephrol 2010 Nov 5;25(11):2241-5. Epub 2010 Jun 5.

Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Ein Karem, Jerusalem, 91120, Israel.

Fibroblast growth factor 23 (FGF23) is a phosphatonin that is secreted by osteocytes and osteoblasts in response to hyperphosphatemia and 1,25-dihydroxyvitamin D (1,25D). It acts on its receptor complex, Klotho-FGFR1c (fibroblast growth factor receptor 1 c-splicing form), in the distal convoluted tubule to repress renal phosphorus reabsorption in the proximal tubule and suppress the renal synthesis of 1,25D. Klotho-FGFR1c is also expressed in the parathyroid glands. FGF23 acts on the receptor complex in the parathyroid glands to decrease parathyroid hormone (PTH) gene expression and PTH secretion through activation of the MAPK pathway. In chronic kidney disease (CKD), both FGF23 and PTH are increased, implying resistance of the parathyroid glands to FGF23. There is a decrease in the Klotho-FGFR1c complex in the parathyroid glands in both experimental CKD and in patients with end-stage renal disease. In addition, in advanced experimental CKD, FGF23 has a decreased ability to inhibit PTH expression.
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http://dx.doi.org/10.1007/s00467-010-1565-3DOI Listing
November 2010

Minireview: the play of proteins on the parathyroid hormone messenger ribonucleic Acid regulates its expression.

Authors:
Tally Naveh-Many

Endocrinology 2010 Apr 23;151(4):1398-402. Epub 2009 Dec 23.

Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel.

PTH regulates serum calcium and phosphate levels and bone strength. The parathyroid is unique in that the trigger for PTH secretion is a low extracellular calcium rather than high calcium as for other hormones. The parathyroid senses small changes in serum calcium through the seven-trans-membrane G protein-coupled calcium receptor to alter PTH secretion. PTH then acts on bone and kidney to correct serum calcium. Parathyroid cells have few secretory granules as compared with other endocrine cells, and therefore PTH production is regulated largely at the levels of PTH gene expression and parathyroid cell proliferation. The regulation of PTH gene expression by changes in calcium and phosphate and in chronic kidney failure is posttranscriptional involving the binding of trans-acting proteins to a defined cis element in the PTH mRNA 3'-untranslated region. These protein-PTH mRNA interactions are orchestrated by the peptidyl-prolyl isomerase Pin1. This review discusses the mechanisms of regulation of PTH mRNA stability determining serum PTH levels and mineral metabolism.
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http://dx.doi.org/10.1210/en.2009-1160DOI Listing
April 2010

Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease.

Kidney Int 2010 Feb 16;77(3):211-8. Epub 2009 Dec 16.

Department of Nephrology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Although fibroblast growth factor 23 (FGF23) acting through its receptor Klotho-FGFR1c decreases parathyroid hormone expression, this hormone is increased in chronic kidney disease despite an elevated serum FGF23. We measured possible factors that might contribute to the resistance of parathyroid glands to FGF23 in rats with the dietary adenine-induced model of chronic kidney disease. Quantitative immunohistochemical and reverse transcription-PCR analysis using laser capture microscopy showed that both Klotho and FGFR1 protein and mRNA levels were decreased in histological sections of the parathyroid glands. Recombinant FGF23 failed to decrease serum parathyroid hormone levels or activate the mitogen-activated protein kinase signaling pathway in the glands of rats with advanced experimental chronic kidney disease. In parathyroid gland organ culture, the addition of FGF23 decreased parathyroid hormone secretion and mRNA levels in control animals or rats with early but not advanced chronic kidney disease. Our results show that because of a downregulation of the Klotho-FGFR1c receptor complex, an increase of circulating FGF23 does not decrease parathyroid hormone levels in established chronic kidney disease. This in vivo resistance is sustained in parathyroid organ culture in vitro.
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http://dx.doi.org/10.1038/ki.2009.464DOI Listing
February 2010

KSRP-PMR1-exosome association determines parathyroid hormone mRNA levels and stability in transfected cells.

BMC Cell Biol 2009 Sep 23;10:70. Epub 2009 Sep 23.

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

Background: Parathyroid hormone (PTH) gene expression is regulated post-transcriptionally through the binding of the trans-acting proteins AU rich binding factor 1 (AUF1), Upstream of N-ras (Unr) and KH-type splicing regulatory protein (KSRP) to an AU rich element (ARE) in PTH mRNA 3'-UTR. AUF1 and Unr stabilize PTH mRNA while KSRP, recruiting the exoribonucleolytic complex exosome, promotes PTH mRNA decay.

Results: PTH mRNA is cleaved by the endoribonuclease polysomal ribonuclease 1 (PMR1) in an ARE-dependent manner. Moreover, PMR1 co-immunoprecipitates with PTH mRNA, the exosome and KSRP. Knock-down of either exosome components or KSRP by siRNAs prevents PMR1-mediated cleavage of PTH mRNA.

Conclusion: PTH mRNA is a target for the endonuclease PMR1. The PMR1 mediated decrease in PTH mRNA levels involves the PTH mRNA 3'-UTR ARE, KSRP and the exosome. This represents an unanticipated mechanism by which the decay of an ARE-containing mRNA is facilitated by KSRP and is dependent on both the exosome and an endoribonuclease.
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http://dx.doi.org/10.1186/1471-2121-10-70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759919PMC
September 2009

The peptidyl-prolyl isomerase Pin1 determines parathyroid hormone mRNA levels and stability in rat models of secondary hyperparathyroidism.

J Clin Invest 2009 Oct 21;119(10):3102-14. Epub 2009 Sep 21.

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

Secondary hyperparathyroidism is a major complication of chronic kidney disease (CKD). In experimental models of secondary hyperparathyroidism induced by hypocalcemia or CKD, parathyroid hormone (PTH) mRNA levels increase due to increased PTH mRNA stability. K-homology splicing regulator protein (KSRP) decreases the stability of PTH mRNA upon binding a cis-acting element in the PTH mRNA 3' UTR region. As the peptidyl-prolyl isomerase (PPIase) Pin1 has recently been shown to regulate the turnover of multiple cytokine mRNAs, we investigated the role of Pin1 in regulating PTH mRNA stability in rat parathyroids and transfected cells. The data generated were consistent with Pin1 being a PTH mRNA destabilizing protein. Initial analysis indicated that Pin1 activity was decreased in parathyroid protein extracts from both hypocalcemic and CKD rats and that pharmacologic inhibition of Pin1 increased PTH mRNA levels posttranscriptionally in rat parathyroid and in transfected cells. Pin1 mediated its effects via interaction with KSRP, which led to KSRP dephosphorylation and activation. In the rat parathyroid, Pin1 inhibition decreased KSRP-PTH mRNA interactions, increasing PTH mRNA levels. Furthermore, Pin1-/- mice displayed increased serum PTH and PTH mRNA levels, suggesting that Pin1 determines basal PTH expression in vivo. These results demonstrate that Pin1 is a key mediator of PTH mRNA stability and indicate a role for Pin1 in the pathogenesis of secondary hyperparathyroidism in individuals with CKD.
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http://dx.doi.org/10.1172/JCI39522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752082PMC
October 2009

Deletion of the vitamin D receptor specifically in the parathyroid demonstrates a limited role for the receptor in parathyroid physiology.

Am J Physiol Renal Physiol 2009 Nov 19;297(5):F1192-8. Epub 2009 Aug 19.

Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hospital, Jerusalem, Israel.

1,25(OH)2D3 decreases parathyroid hormone (PTH) gene transcription through the vitamin D receptor (VDR). Total body VDR(-/-) mice have high PTH levels, hypocalcemia, hypophosphatemia, and bone malformations. To investigate PTH regulation by the VDR specifically in the parathyroid, we generated parathyroid-specific VDR knockout mice (PT-VDR(-/-)). In both strains, there was a decrease in parathyroid calcium receptor (CaR) levels. The number of proliferating parathyroid cells was increased in the VDR(-/-) mice but not in the PT-VDR(-/-) mice. Serum PTH levels were moderately but significantly increased in the PT-VDR(-/-) mice with normal serum calcium levels. The sensitivity of the parathyroid glands of the PT-VDR(-/-) mice to calcium was intact as measured by serum PTH levels after changes in serum calcium. This indicates that the reduced CaR in the PT-VDR(-/-) mice enables a physiologic response to serum calcium. Serum C-terminal collagen crosslinks, a marker of bone resorption, were increased in the PT-VDR(-/-) mice with no change in the bone formation marker, serum osteocalcin, consistent with a resorptive effect due to the increased serum PTH levels in the PT-VDR(-/-) mice. Therefore, deletion of the VDR specifically in the parathyroid decreases parathyroid CaR expression and only moderately increases basal PTH levels, suggesting that the VDR has a limited role in parathyroid physiology.
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http://dx.doi.org/10.1152/ajprenal.00360.2009DOI Listing
November 2009

The complex regulation of HIC (Human I-mfa domain containing protein) expression.

PLoS One 2009 Jul 7;4(7):e6152. Epub 2009 Jul 7.

Department of Biological Chemistry, Institute of Life Science, The Hebrew University, Jerusalem, Israel.

Human I-mfa domain containing protein (HIC) differentially regulates transcription from viral promoters. HIC affects the Wnt pathway, the JNK/SAPK pathway and the activity of positive transcription elongation factor-b (P-TEFb). Studies exploring HIC function in mammalian cells used ectopically expressed HIC due to undetected endogenous HIC protein. HIC mRNA contains exceptionally long 5' and 3' untranslated regions (UTRs) compared to the average length of mRNA UTRs. Here we show that HIC protein is subject to strict repression at multiple levels. The HIC mRNA UTRs reduce the expression of HIC or of a reporter protein: The HIC 3'-UTR decreases both HIC and reporter mRNA levels, whereas upstream open reading frames located in the 5'-UTR repress the translation of HIC or of the reporter protein. In addition, ectopically expressed HIC protein is degraded by the proteasome, with a half-life of approximately 1 h, suggesting that upon activation, HIC expression in cells may be transient. The strict regulation of HIC expression at the levels of mRNA stability, translation efficiency and protein stability suggests that expression of the HIC protein and its involvement in the various pathways is required only under specific cellular conditions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006152PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701633PMC
July 2009

Human PTH gene regulation in vivo using transgenic mice.

Am J Physiol Renal Physiol 2009 Sep 1;297(3):F713-9. Epub 2009 Jul 1.

Nephrology Services, Hadassah Hebrew University Medical Center, P. O. Box 12000, Jerusalem, Israel 91120.

To study the regulation of the human PTH (hPTH) gene in vivo, we generated transgenic mice with the hPTH gene expressed in the mouse parathyroid using a bacterial artificial chromosome (BAC) containing the hPTH gene within its 144-kb chromosomal region. The BAC construct maintains the native hPTH gene surrounding sequences and isolates it from positional effects. The transgenic mice had normal levels of serum mouse PTH (mPTH) in addition to both intact and bioactive hPTH. Despite the presence of both mPTH and hPTH, serum calcium and 1,25(OH)(2) vitamin D levels were normal. The lack of response to hPTH may be due to tachyphylaxis of the mPTH receptor (PTH1R) and/or impaired recognition of the mPTH1R. In contrast, the regulation of hPTH levels in the mouse was intact. A calcium-depleted diet increased serum mPTH and both intact and bioactive hPTH. mPTH and hPTH mRNA levels were also markedly increased. The calcimimetic R-568 dramatically decreased mPTH and hPTH serum levels. Administered recombinant fibroblast growth factor (FGF)23 decreased hPTH. Therefore, the regulation of hPTH gene expression and serum hPTH levels is intact in the transgenic mice, indicating preservation of the signal transduction of the parathyroid calcium receptor and the Klotho-FGF receptor between mouse and man.
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http://dx.doi.org/10.1152/ajprenal.00161.2009DOI Listing
September 2009

The calcium-sensing receptor regulates parathyroid hormone gene expression in transfected HEK293 cells.

BMC Biol 2009 Apr 27;7:17. Epub 2009 Apr 27.

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

Background: The parathyroid calcium receptor determines parathyroid hormone secretion and the response of parathyroid hormone gene expression to serum Ca2+ in the parathyroid gland. Serum Ca2+ regulates parathyroid hormone gene expression in vivo post-transcriptionally affecting parathyroid hormone mRNA stability through the interaction of trans-acting proteins to a defined cis element in the parathyroid hormone mRNA 3'-untranslated region. These parathyroid hormone mRNA binding proteins include AUF1 which stabilizes and KSRP which destabilizes the parathyroid hormone mRNA. There is no parathyroid cell line; therefore, we developed a parathyroid engineered cell using expression vectors for the full-length human parathyroid hormone gene and the human calcium receptor.

Results: Co-transfection of the human calcium receptor and the human parathyroid hormone plasmid into HEK293 cells decreased parathyroid hormone mRNA levels and secreted parathyroid hormone compared with cells that do not express the calcium receptor. The decreased parathyroid hormone mRNA correlated with decreased parathyroid hormone mRNA stability in vitro, which was dependent upon the 3'-UTR cis element. Moreover, parathyroid hormone gene expression was regulated by Ca2+ and the calcimimetic R568, in cells co-transfected with the calcium receptor but not in cells without the calcium receptor. RNA immunoprecipitation analysis in calcium receptor-transfected cells showed increased KSRP-parathyroid hormone mRNA binding and decreased binding to AUF1. The calcium receptor led to post-translational modifications in AUF1 as occurs in the parathyroid in vivo after activation of the calcium receptor.

Conclusion: The expression of the calcium receptor is sufficient to confer the regulation of parathyroid hormone gene expression to these heterologous cells. The calcium receptor decreases parathyroid hormone gene expression in these engineered cells through the parathyroid hormone mRNA 3'-UTR cis element and the balanced interactions of the trans-acting factors KSRP and AUF1 with parathyroid hormone mRNA, as in vivo in the parathyroid. This is the first demonstration that the calcium receptor can regulate parathyroid hormone gene expression in heterologous cells.
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http://dx.doi.org/10.1186/1741-7007-7-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2681451PMC
April 2009

Phosphate and the parathyroid.

Kidney Int 2009 May 7;75(9):898-905. Epub 2009 Jan 7.

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

The phosphate (Pi) retention in patients with chronic kidney disease leads to secondary hyperparathyroidism (2HPT). 2HPT is the physiological response of the parathyroid not only to Pi retention but also to decreased synthesis of 1,25(OH)(2) vitamin D, and the attendant hypocalcemia. 2HPT is characterized by increased PTH synthesis, secretion, and parathyroid cell proliferation. Extracellular fluid (ECF) Ca(2+) is recognized by the parathyroid calcium receptor and a small decrease in the ECF Ca(2+) results in relaxation of the calcium receptor and allows the unrestrained secretion and synthesis of PTH and in the longer term, parathyroid cell proliferation. Both 1,25(OH)(2) vitamin D and fibroblast growth factor 23 inhibit PTH gene expression and secretion. Secondary hyperparathyroidism can initially be controlled by a single therapeutic intervention, such as a Pi-restricted diet, a calcimimetic, or an active vitamin D analog. In this review we discuss the mechanisms whereby Pi regulates the parathyroid. Pi has a direct effect on the parathyroid which requires intact parathyroid tissue architecture. The effect of Pi, as of Ca(2+), on PTH gene expression is post-transcriptional and involves the regulated interaction of parathyroid cytosolic proteins to a defined cis acting sequence in the PTH mRNA. Changes in serum Ca(2+) or Pi regulate the activity of trans acting interacting proteins in the parathyroid, which alters their binding to a defined 26 nucleotide cis acting instability sequence in the PTH mRNA 3'-untranslated region. The trans factors are either stabilizing or destabilizing factors and their regulated binding to the PTH cis acting element determines the PTH mRNA half-life. The responses of the parathyroid to changes in serum Pi are now being revealed but the sensing mechanisms remain a mystery.
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http://dx.doi.org/10.1038/ki.2008.642DOI Listing
May 2009

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

Am J Physiol Renal Physiol 2009 Apr 7;296(4):F795-800. Epub 2009 Jan 7.

Minerva Center for Calcium and Bone Metabolism, Hadassah Hebrew Univ. Medical Center, P.O. Box 12000, Jerusalem, Israel 91120.

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.
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http://dx.doi.org/10.1152/ajprenal.90625.2008DOI Listing
April 2009

Fibroblast growth factor 23 acts on the parathyroid to decrease parathyroid hormone secretion.

Curr Opin Nephrol Hypertens 2008 Jul;17(4):363-7

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

Purpose Of Review: The aim of this article is to describe the intriguing action of fibroblast growth factor 23 on the parathyroid.

Recent Findings: Fibroblast growth factor 23 inhibits renal phosphate reabsorption and calcitriol production. It is the principal phosphaturic factor in a bone-kidney axis coordinating systemic phosphate homeostasis and bone mineralization. Fibroblast growth factor 23 acts at its target tissues by binding to the Klotho-FGFR1c complex and it has recently been confirmed that the fibroblast growth factor 23 receptor is present not only in renal tissue but also in the parathyroid. Fibroblast growth factor 23 leads to a decrease in parathyroid hormone mRNA and serum parathyroid hormone levels by the mitogen-activated protein kinase pathway both in vivo and in vitro.

Summary: Fibroblast growth factor 23 is secreted by osteocytes and acts through its receptor the heterodimer of Klotho-FGFR1c in the kidney and parathyroid. In the kidney it leads to phosphaturia and decreased calcitriol synthesis, and in the parathyroid it activates the mitogen-activated protein kinase pathway to decrease parathyroid hormone gene expression and secretion. The decreased parathyroid hormone levels would then also contribute to a decrease in calcitriol synthesis. A bone-kidney-parathyroid hormonal network is now apparent which regulates phosphate, calcium and calcitriol homeostasis. Fibroblast growth factor 23 is the major factor regulating phosphate, and parathyroid hormone the major factor for calcium and calcitriol balances between these factors.
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http://dx.doi.org/10.1097/MNH.0b013e328303e172DOI Listing
July 2008

The mRNA decay promoting factor K-homology splicing regulator protein post-transcriptionally determines parathyroid hormone mRNA levels.

FASEB J 2008 Oct 26;22(10):3458-68. Epub 2008 Jun 26.

Minerva Center for Calcium and Bone Metabolism, Hadassah Hebrew University Medical Center, PO Box 12000, Jerusalem, Israel 91120.

Serum calcium and phosphate concentrations and experimental chronic kidney failure control parathyroid hormone (PTH) gene expression post-transcriptionally through regulated binding of the trans-acting proteins AUF1 and upstream of N-ras (Unr) to an AU-rich element (ARE) in PTH mRNA 3'-untranslated region (3'UTR). We show that the mRNA decay promoting K-homology splicing regulator protein (KSRP) binds to PTH mRNA in intact parathyroid glands and in transfected cells. This binding is decreased in glands from calcium-depleted or experimental chronic kidney failure rats in which PTH mRNA is more stable compared to parathyroid glands from control and phosphorus-depleted rats in which PTH mRNA is less stable. PTH mRNA decay depends on the KSRP-recruited exosome in parathyroid extracts. In transfected cells, KSRP overexpression and knockdown experiments show that KSRP decreases PTH mRNA stability and steady-state levels through the PTH mRNA ARE. Overexpression of isoform p45 of the PTH mRNA stabilizing protein AUF1 blocks KSRP-PTH mRNA binding and partially prevents the KSRP mediated decrease in PTH mRNA levels. Therefore, calcium or phosphorus depletion, as well as chronic kidney failure, regulate the interaction of KSRP and AUF1 with PTH mRNA and its half-life. Our data indicate a novel role for KSRP in PTH gene expression.
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http://dx.doi.org/10.1096/fj.08-107250DOI Listing
October 2008

The parathyroid is a target organ for FGF23 in rats.

J Clin Invest 2007 Dec;117(12):4003-8

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

Phosphate homeostasis is maintained by a counterbalance between efflux from the kidney and influx from intestine and bone. FGF23 is a bone-derived phosphaturic hormone that acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. FGF23 signals with highest efficacy through several FGF receptors (FGFRs) bound by the transmembrane protein Klotho as a coreceptor. Since most tissues express FGFR, expression of Klotho determines FGF23 target organs. Here we identify the parathyroid as a target organ for FGF23 in rats. We show that the parathyroid gland expressed Klotho and 2 FGFRs. The administration of recombinant FGF23 led to an increase in parathyroid Klotho levels. In addition, FGF23 activated the MAPK pathway in the parathyroid through ERK1/2 phosphorylation and increased early growth response 1 mRNA levels. Using both rats and in vitro rat parathyroid cultures, we show that FGF23 suppressed both parathyroid hormone (PTH) secretion and PTH gene expression. The FGF23-induced decrease in PTH secretion was prevented by a MAPK inhibitor. These data indicate that FGF23 acts directly on the parathyroid through the MAPK pathway to decrease serum PTH. This bone-parathyroid endocrine axis adds a new dimension to the understanding of mineral homeostasis.
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http://dx.doi.org/10.1172/JCI32409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2066196PMC
December 2007

Regulation of parathyroid hormone mRNA stability by calcium, phosphate and uremia.

Curr Opin Nephrol Hypertens 2007 Jul;16(4):305-10

Minerva Center for Calcium and Bone Metabolism, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Purpose Of Review: This review focuses on the regulation of parathyroid hormone gene expression by dietary-induced hypocalcemia, hypophosphatemia and uremia. Understanding the mechanism by which calcium and phosphate regulate parathyroid hormone gene expression is important for both normal physiology and in pathological states, especially chronic kidney disease.

Recent Findings: Calcium and phosphate regulate parathyroid hormone secretion, gene expression and, if prolonged, parathyroid cell proliferation. Chronic kidney disease is characterized by a high serum phosphate level that often leads to secondary hyperparathyroidism. In the rat, regulation of parathyroid hormone gene expression by calcium, phosphate and uremia is posttranscriptional, affecting mRNA stability. Differences in binding of protective trans-acting proteins to a conserved protein-binding cis-acting instability element in the parathyroid hormone mRNA 3'-untranslated region alter parathyroid hormone mRNA stability. Two trans-acting proteins - adenosine-uridine rich binding factor 1 and Up-stream of N-ras- stabilize parathyroid hormone mRNA in vivo and in vitro. Parathyroid hormone mRNA also interacts with mRNA decay-promoting proteins and ribonucleases that lead to parathyroid hormone mRNA degradation.

Summary: Calcium, phosphate and uremia determine parathyroid hormone mRNA stability through the binding of the protective factors adenosine-uridine rich binding factor 1 and Up-stream of N-ras and the recruitment of a degradation complex that cleaves parathyroid hormone mRNA.
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http://dx.doi.org/10.1097/MNH.0b013e3281c55edeDOI Listing
July 2007