Publications by authors named "Justin Silver"

51 Publications

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

The Effect of Intramural Myomas Without an Intracavity Component on In Vitro Fertilization Outcomes in Single Fresh Blastocyst Transfer Cycles.

J Minim Invasive Gynecol 2018 Nov - Dec;25(7):1241-1248. Epub 2018 Mar 9.

McGill University Health Center, Montreal, Quebec, Canada.

Study Objective: To assess clinical pregnancy rate (CPR) and live birth rate (LBR) in the presence of non-cavity-deforming intramural myomas in single fresh blastocyst transfer cycles.

Design: Retrospective cohort study (Canadian Task Force classification II-2).

Setting: Academic fertility center.

Patients: A total of 929 fresh single blastocyst transfer cycles were included, 94 with only non-cavity-distorting intramural myomas and 764 without myomas. Cleavage embryo transfers were excluded to reduce bias based on embryo quality.

Interventions: None.

Measurements And Main Results: CPR and LBR were assessed. There were no differences noted in gravidity, parity, or body mass index between patients with myomas and those without myomas. Women with myomas required higher doses of gonadotropins (mean, 2653 ± 404 IU vs 2350 ± 1368 IU; p = .04) than women without myomas. However, the total number of mature oocytes collected and the total number of blastocysts created were similar. CPR (47% vs 32%; p = .005) and LBR (37.8% vs 25.5%; p = .02) were lower in patients who had intramural myomas compared with those without myomas. CPR and LBR were significantly reduced in the presence of even 1 myoma (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.33-0.83 and OR, 0.56; 95% CI, 0.35-0.92, respectively). In patients with myomas >1.5 cm, LBR was also significantly reduced, even after adjusting for age, smoking, quality of embryo transferred, antral follicle count, and dose of gonadotropins (OR, 0.53; 95% CI, 0.29-0.97). This LBR finding was not significant if all myomas were included (including those <1.5 cm in diameter), but CPR was still significantly reduced.

Conclusion: Relatively small (>1.5 cm) non-cavity-distorting intramural myomas negatively affect CPR and LBR in in vitro fertilization cycles, even in the presence of only 1 myoma.
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http://dx.doi.org/10.1016/j.jmig.2018.03.005DOI Listing
August 2019

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

Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial.

JAMA 2017 01;317(2):156-164

Stanford University, Stanford, California.

Importance: Secondary hyperparathyroidism contributes to extraskeletal calcification and is associated with all-cause and cardiovascular mortality. Control is suboptimal in the majority of patients receiving hemodialysis. An intravenously (IV) administered calcimimetic could improve adherence and reduce adverse gastrointestinal effects.

Objective: To evaluate the relative efficacy and safety of the IV calcimimetic etelcalcetide and the oral calcimimetic cinacalcet.

Design, Setting, And Participants: A randomized, double-blind, double-dummy active clinical trial was conducted comparing IV etelcalcetide vs oral placebo and oral cinacalcet vs IV placebo in 683 patients receiving hemodialysis with serum parathyroid hormone (PTH) concentrations higher than 500 pg/mL on active therapy at 164 sites in the United States, Canada, Europe, Russia, and New Zealand. Patients were enrolled from August 2013 to May 2014, with end of follow-up in January 2015.

Interventions: Etelcalcetide intravenously and oral placebo (n = 340) or oral cinacalcet and IV placebo (n = 343) for 26 weeks. The IV study drug was administered 3 times weekly with hemodialysis; the oral study drug was administered daily.

Main Outcomes And Measures: The primary efficacy end point was noninferiority of etelcalcetide at achieving more than a 30% reduction from baseline in mean predialysis PTH concentrations during weeks 20-27 (noninferiority margin, 12.0%). Secondary end points included superiority in achieving biochemical end points (>50% and >30% reduction in PTH) and self-reported nausea or vomiting.

Results: The mean (SD) age of the trial participants was 54.7 (14.1) years and 56.2% were men. Etelcalcetide was noninferior to cinacalcet on the primary end point. The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30% between the 198 of 343 patients (57.7%) randomized to receive cinacalcet and the 232 of 340 patients (68.2%) randomized to receive etelcalcetide was -10.5% (95% CI, -17.5% to -3.5%, P for noninferiority, <.001; P for superiority, .004). One hundred seventy-eight patients (52.4%) randomized to etelcalcetide achieved more than 50% reduction in PTH concentrations compared with 138 patients (40.2%) randomized to cinacalcet (P = .001; difference in proportions, 12.2%; 95% CI, 4.7% to 19.5%). The most common adverse effect was decreased blood calcium (68.9% vs 59.8%).

Conclusions And Relevance: Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, the use of etelcalcetide was not inferior to cinacalcet in reducing serum PTH concentrations over 26 weeks; it also met superiority criteria. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety.

Trial Registration: clinicaltrials.gov Identifier: NCT1896232.
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http://dx.doi.org/10.1001/jama.2016.19468DOI Listing
January 2017

Effect of Etelcalcetide vs Placebo on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: Two Randomized Clinical Trials.

JAMA 2017 01;317(2):146-155

Stanford University, Stanford, California.

Importance: Secondary hyperparathyroidism contributes to extraskeletal complications in chronic kidney disease.

Objective: To evaluate the effect of the intravenous calcimimetic etelcalcetide on serum parathyroid hormone (PTH) concentrations in patients receiving hemodialysis.

Design, Setting, And Participants: Two parallel, phase 3, randomized, placebo-controlled treatment trials were conducted in 1023 patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism. Trial A was conducted in 508 patients at 111 sites in the United States, Canada, Europe, Israel, Russia, and Australia from March 12, 2013, to June 12, 2014; trial B was conducted in 515 patients at 97 sites in the same countries from March 12, 2013, to May 12, 2014.

Interventions: Intravenous administration of etelcalcetide (n = 503) or placebo (n = 513) after each hemodialysis session for 26 weeks.

Main Outcomes And Measures: The primary efficacy end point was the proportion of patients achieving greater than 30% reduction from baseline in mean PTH during weeks 20-27. A secondary efficacy end point was the proportion of patients achieving mean PTH of 300 pg/mL or lower.

Results: The mean age of the 1023 patients was 58.2 (SD, 14.4) years and 60.4% were men. Mean PTH concentrations at baseline and during weeks 20-27 were 849 and 384 pg/mL vs 820 and 897 pg/mL in the etelcalcetide and placebo groups, respectively, in trial A; corresponding values were 845 and 363 pg/mL vs 852 and 960 pg/mL in trial B. Patients randomized to etelcalcetide were significantly more likely to achieve the primary efficacy end point: in trial A, 188 of 254 (74.0%) vs 21 of 254 (8.3%; P < .001), for a difference in proportions of 65.7% (95% CI, 59.4%-72.1%) and in trial B, 192 of 255 (75.3%) vs 25 of 260 (9.6%; P < .001), for a difference in proportions of 65.7% (95% CI, 59.3%-72.1%). Patients randomized to etelcalcetide were significantly more likely to achieve a PTH level of 300 pg/mL or lower: in trial A, 126 of 254 (49.6%) vs 13 of 254 (5.1%; P < .001), for a difference in proportions of 44.5% (95% CI, 37.8%-51.2%) and in trial B, 136 of 255 (53.3%) vs 12 of 260 (4.6%; P < .001), for a difference in proportions of 48.7% (95% CI, 42.1%-55.4%). In trials A and B, respectively, patients receiving etelcalcetide had more muscle spasms (12.0% and 11.1% vs 7.1% and 6.2% with placebo), nausea (12.4% and 9.1% vs 5.1% and 7.3%), and vomiting (10.4% and 7.5% vs 7.1% and 3.1%).

Conclusions And Relevance: Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, use of etelcalcetide compared with placebo resulted in greater reduction in serum PTH over 26 weeks. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety.

Trial Registration: clinicaltrials.gov Identifiers: NCT01788046.
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http://dx.doi.org/10.1001/jama.2016.19456DOI Listing
January 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 PTH--double agents at the heart of CKD.

Nephrol Dial Transplant 2012 May 23;27(5):1715-20. Epub 2012 Mar 23.

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

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http://dx.doi.org/10.1093/ndt/gfs050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471546PMC
May 2012

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

Removing the paperwork from physical therapy.

Authors:
Justin Silver

Healthc Inform 2011 Apr;28(4):18, 20

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April 2011

CKD-MBD: comfort in the trough of the U.

Nephrol Dial Transplant 2011 Jun 5;26(6):1764-6. Epub 2011 May 5.

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http://dx.doi.org/10.1093/ndt/gfr205DOI Listing
June 2011

Calcimimetics, vitamin D and ADVANCE in the management of CKD-MBD.

Nephrol Dial Transplant 2011 Apr 21;26(4):1117-9. Epub 2011 Mar 21.

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http://dx.doi.org/10.1093/ndt/gfq862DOI Listing
April 2011

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

Keeping divalent ions in their proper place.

Curr Opin Nephrol Hypertens 2010 Jul;19(4):333-4

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http://dx.doi.org/10.1097/MNH.0b013e32833ac53dDOI Listing
July 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

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

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

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

Vitamin D supplementation after renal transplantation: how much vitamin D should we prescribe?

Kidney Int 2009 Mar;75(6):576-8

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

Vitamin D deficiency is common in patients with chronic kidney disease after renal transplantation. Vitamin D, essential for mineral and bone metabolism, also has myriad beneficial autocrine effects on intact immune responses and defense against infection, as well as suppression of malignant changes. Supplementation with oral parental vitamin D could correct this problem. Courbebaisse et al. define how much oral vitamin D to prescribe to renal allograft recipients.
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http://dx.doi.org/10.1038/ki.2008.492DOI Listing
March 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