The Experts below are selected from a list of 7911 Experts worldwide ranked by ideXlab platform
Eduardo Slatopolsky - One of the best experts on this subject based on the ideXlab platform.
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Calcium-sensing receptor expression is regulated by glial Cells missing-2 in human Parathyroid Cells.
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2009Co-Authors: Masahide Mizobuchi, Eduardo Slatopolsky, Cynthia S. Ritter, Irina Krits, Gregorio A. Sicard, Alex J BrownAbstract:Glial Cells missing-2 (Gcm2) is the key regulating transcription factor for Parathyroid gland development. The continued expression of high levels of Gcm2 in mature Parathyroid glands suggests that it is required for maintenance of Parathyroid Cell differentiation. The role of Gcm2 in Parathyroid Cell physiology, however, has not been fully studied. In this study, we examined the effects of Gcm2 silencing on cultured human Parathyroid Cells. Collagenase-dispersed human Parathyroid Cells from patients with chronic kidney disease were placed in monolayer cultures and infected with lentivirus expressing shRNA for human Gcm2. Seventy-two hours after infection, mRNA was processed and analyzed for Gcm2, PTH, vitamin D receptor (VDR), calcium-sensing receptor (CaR), 25-hydroxyvitamin D3 1-α-hydroxylase (1-OHase), and proliferating Cell nuclear antigen (PCNA) by real-time PCR (qPCR). Protein expression of affected genes was analyzed by immunoblot 72 h after infection. Gcm2 mRNA and protein were decreased by 74.2 ± 12.2% (SD; n = 3 experiments; p < 0.01) and 67.5 ± 15.7% (n = 2; p < 0.01), respectively. CaR mRNA and protein were reduced by 47.8 ± 21.1% (n = 3; p < 0.01) and 48.1 ± 4.3% (n = 3; p < 0.01), respectively. However, VDR, PTH, 1-OHase, and PCNA were not significantly affected by Gcm2 silencing. Further analysis of CaR mRNA indicated that transcripts containing exon 1B, derived by transcription from CaR promoter 2, were downregulated (58.8 ± 19.27%; n = 3; p < 0.05) by Gcm2 silencing. Exon 1A–containing transcripts from promoter 1 were expressed at very low levels in the cultures. These results indicate that one function of Gcm2 is to maintain high levels of CaR expression in Parathyroid Cells.
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p21waf1 and transforming growth factor α mediate dietary phosphate regulation of Parathyroid Cell growth
Kidney International, 2001Co-Authors: Adriana Dusso, Alex J Brown, Tricia Pavlopoulos, Lech Naumovich, Jane Finch, Jeremiah J Morrissey, Eduardo SlatopolskyAbstract:p21 WAF1 and transforming growth factor-α mediate dietary phosphate regulation of Parathyroid Cell growth. Background The Parathyroid (PT) hyperplasia induced by renal failure can be further enhanced by high dietary phosphate (P) or completely abolished by P restriction. To identify potential mechanisms mediating these opposing effects of dietary P on PT growth, this study first focused on p21 WAF1 (p21) because high P reduces while low P enhances serum 1,25-dihydroxyvitamin D, whose potent antiproliferative properties result from the induction of p21. In addition to reducing p21, high P-induced PT growth could result from increased PT expression of the growth promoter transforming growth factor-α (TGF-α), known to be elevated in hyperplastic and adenomatous human PT glands. Methods The time course for dietary P regulation of PT expression of TGF-α and p21 was assessed for seven days after 5/6 nephrectomy in rats and correlated with the degree of PT hyperplasia and secondary hyperParathyroidism. Results In P-restricted 5/6 nephrectomized rats, PT-p21 mRNA and protein increased by day 2, independent of changes in serum 1,25-dihydroxyvitamin D, and remained higher than in the high P counterparts for up to seven days. The PT hyperplasia of the high P group could not be attributed to a reduction of PT-p21 expression from normal control values. Instead, PT–TGF-α protein was higher in uremic rats compared with normal controls and increased further with high dietary P intake. PT levels of proliferating Cell nuclear antigen (PCNA), an index of Cell mitoses, correlated inversely with p21 and directly with TGF-α. Consistent with these findings, PT gland size and serum PT hormone levels, similar in both dietary groups at day 2, were higher in the high P group by day 5. Induction of p21 by low P and of TGF-α by high P was specific for the PT glands. Dietary P had no effect either on intestinal growth or p21 or TGF-α protein content. Conclusions These findings suggest that low P induction of p21 could prevent PT hyperplasia in early uremia, whereas high P enhancement of TGF-α may function as an autocrine signal to stimulate growth further.
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the role of phosphorus in the development of secondary hyperParathyroidism and Parathyroid Cell proliferation in chronic renal failure
The American Journal of the Medical Sciences, 1999Co-Authors: Eduardo Slatopolsky, Adriana Dusso, Alex J BrownAbstract:Hyperplasia of the Parathyroid glands and high levels of Parathyroid hormone (PTH) are among the most consistent findings in patients with chronic renal failure. In early renal failure, alterations in vitamin D metabolism play a key role in the development of secondary hyperParathyroidism. Low levels of calcitriol and decreased expression of the vitamin D responsive element may allow greater synthesis and secretion of PTH. Phosphorus independent of serum calcium and calcitriol increases PTH synthesis and secretion by a post-transcriptional mechanism. Studies in vivo in uremic rats demonstrated that an increase in dietary phosphorus induces Parathyroid gland hyperplasia. If the rats are then fed a low-phosphorus diet, the levels of serum PTH return to normal; however, the size of the Parathyroid glands remains enlarged. No apoptosis was observed in the glands. To further characterize the effects of phosphorus on PTH synthesis and secretion, intact rat Parathyroid glands were metabolically labeled during a 4-hour incubation in methionine-free medium containing 1.25 mM Ca2 +, [35S]methionine, and either 2.8 mM or 0.2 mM phosphorus. Total PTH secretion, as measured in the medium, was increased more than 6-fold in glands incubated in high-phosphorus medium compared with glands incubated in the low-phosphorus medium. Thus, in the past 20 years, numerous investigators have provided strong evidence for the action of phosphorus on PTH secretion. Unfortunately, the absence of a Parathyroid Cell line is slowing the progress in understanding the molecular mechanism(s) involved in phosphorus regulation of PTH.
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decreased calcium sensing receptor expression in hyperplastic Parathyroid glands of uremic rats role of dietary phosphate
Kidney International, 1999Co-Authors: Alex J Brown, Jane Finch, Cynthia S. Ritter, Eduardo SlatopolskyAbstract:Decreased calcium-sensing receptor expression in hyperplastic Parathyroid glands of uremic rats: Role of dietary phosphate. Background The abnormal control of Parathyroid hormone secretion in chronic renal failure is attributed, in part, to down-regulation of the calcium-sensing receptor (CaR) in hyperplastic Parathyroid tissue. The cause of this down-regulation is unknown. Here we examined the roles of uremia and Parathyroid hyperplasia on Parathyroid gland (PTG) CaR expression in the rat model of renal failure. Methods Rats made uremic by 5/6 nephrectomy were maintained for one month on diets containing 0.2% P (low phosphate), 0.5% P (normal phosphate) or 1.2% P (high phosphate); intact rats (controls) were maintained on the normal-phosphate diet. Results CaR mRNA was reduced only in uremic rats fed the high-phosphate diet (55% less than in controls, P P P Conclusion These results suggest that CaR down-regulation cannot be attributed to uremia per se, but rather, is associated with Parathyroid Cell proliferation. Furthermore, dietary phosphate restriction prevents both the Parathyroid hyperplasia and decreased CaR expression in renal failure.
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Loss of Calcium Responsiveness in Cultured Bovine Parathyroid Cells Is Associated with Decreased Calcium Receptor Expression
Biochemical and biophysical research communications, 1995Co-Authors: Alex J Brown, Edward M. Brown, Min Zhong, Cynthia Ritter, Eduardo SlatopolskyAbstract:Suppression of PTH secretion by extraCellular calcium is mediated by a plasma membrane calcium receptor (CaR). However, primary cultures of bovine Parathyroid Cells are known to quickly lose their responsiveness to extraCellular calcium. The present study was designed to determine if the loss of calcium responsiveness is due to changes in CaR expression. In primary monolayer cultures of Parathyroid Cells, calcium-mediated suppression of PTH was still evident after 24 hours in culture but was completely absent after 6 days. This was preceded by a 75% drop in CaR mRNA content within 24 hours. CaR mRNA levels remained low for the 6-day culture. Earlier time points, examined in Parathyroid Cell suspensions, showed a 70% drop in CaR mRNA by 4 hours after collagenase-dispersion of the glands and an 85% drop after 24 hours. The decreased expression of CaR mRNA was not influenced by altering medium serum, calcium, or 1,25-dihydroxyvitamin D3. Our results indicate that the loss of responsiveness of cultured Parathyroid Cells to calcium is due to decreased CaR mRNA and, presumably, CaR protein expression.
Mariano Rodriguez - One of the best experts on this subject based on the ideXlab platform.
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Engineering Parathyroid Cells to treat secondary hyperParathyroidism
Kidney international, 2009Co-Authors: Mariano Rodriguez, Julio M. Martínez-moreno, Yolanda AlmadenAbstract:Kanai et al. used antisense technology to reduce excessive PTH production. The authors have overcome technical difficulties to demonstrate that, by strategies of RNA interference, a steady reduction of PTH secretion can be induced in cultured Parathyroid-Cell spheroids and in athymic nude mice with hyperplastic Parathyroid Cells transplanted from patients with secondary hyperParathyroidism.
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Regulation of Parathyroid function in chronic renal failure
Journal of Bone and Mineral Metabolism, 2006Co-Authors: Mariano Rodriguez, Sagrario Cañadillas, Ignacio Lopez, Escolástico Aguilera-tejero, Yolanda AlmadenAbstract:This review summarizes the factors involved in the development of hyperParathyroidism secondary (2nd-HPTH) to chronic kidney disease (CKD). Calcium and calcitriol act on their respective specific Parathyroid Cell receptors to inhibit Parathyroid function. As well as the well-known effect of calcium and calcitriol on Parathyroid Cell function, there is experimental work that demonstrates that phosphate, changes in pH, PTHrP, estrogens, and some cytokines also have an effect on PTH secretion. These factors are relevant in patients with chronic kidney disease. However, low calcium, vitamin D deficiency, and an accumulation of phosphate due to the decrease in renal function are the main pathogenic factors involved in the pathogenesis of 2nd-HPTH in CKD patients.
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Effects of uremic ultrafiltrate on the regulation of the Parathyroid Cell cycle by calcitriol
Kidney international, 2003Co-Authors: Antonio Canalejo, Yolanda Almaden, Rita De Smet, Griet Glorieux, Bartolome Garfia, Fernando Luque, Raymond Vanholder, Mariano RodriguezAbstract:Effects of uremic ultrafiltrate on the regulation of the Parathyroid Cell cycle by calcitriol. Background Calcitriol (CTR) is used in the treatment of hyperParathyroidism secondary to renal failure because it decreases Parathyroid hormone (PTH) synthesis and Parathyroid Cell proliferation. Previous studies in tissues other than Parathyroids have demonstrated that uremic factors affect the action of CTR on the target Cells. We questioned whether the uremic milieu interferes with the inhibition of Parathyroid Cell proliferation by CTR. Methods Studies were performed in vitro using freshly excised normal dog Parathyroid tissue incubated for 24 hours with and without CTR and in the presence of either total uremic ultrafiltrate (UUF) from uremic patients or high-pressure liquid chromatography (HPLC)-derived fractions (hydrophilic compounds eluting early and hydrophobic compounds eluting late) of this UUF (F1 to F4). Parathyroid Cell proliferation was assessed by flow cytometry. Results The addition of CTR 10 -8 and 10 -7 mol/L to Parathyroid tissue produced an inhibition of the proliferation that was prevented in the presence of UUF. In a medium containing CTR 10 -8 mol/L, the addition of F1, F2 and F3, but not F4, prevented the CTR-induced inhibition of Parathyroid Cell proliferation. With CTR 10 -7 mol/L, the inhibition of proliferation was observed even in the presence of F1, F2 and also F4, but was prevented by F3. Uric acid (7 mg/dL), indoxyl sulfate (5 mg/dL) and p-cresol (1.4 mg/dL), which coeluted with F1, F2 and F4, respectively, did not interfere with the inhibitory action of CTR 10 -7 mol/L; however, the addition of phenol (0.14 mg/dL), which coeluted with F3, prevented the CTR-induced inhibition of Parathyroid Cell proliferation. Conclusions The presence of uremic toxins prevents the inhibition of Parathyroid Cell proliferation induced by calcitriol.
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The in vitro effect of calcitriol on Parathyroid Cell proliferation and apoptosis.
Journal of The American Society of Nephrology, 2000Co-Authors: Antonio Canalejo, Yolanda Almaden, Blanca Ramos, Arnold J. Felsenfeld, Jose Maria Campistol, Jose C. Gomez-villamandos, Vanessa Torregrosa, Mariano RodriguezAbstract:Calcitriol treatment is used to reduce Parathyroid hormone levels in azotemic patients with secondary hyperpara- thyroidism (HPT). Whether long-term calcitriol administration reduces Parathyroid gland size in patients with severe second- ary hyperParathyroidism is not clear. The aim of the study was to evaluate in vitro the effect of calcitriol on Parathyroid Cell proliferation and apoptosis in normal Parathyroid glands and in adenomatous and hyperplastic human Parathyroid glands. Freshly harvested Parathyroid glands from normal dogs and hyperplastic and adenomatous glands from patients with sec- ondary (2°) and primary (1°) HPT undergoing Parathyroidec- tomy were studied. Flow cytometry was used to quantify the Cell cycle and apoptosis of Parathyroid Cells. Apoptosis was also evaluated by DNA electrophoresis and light and electron microscopy. In normal dog Parathyroid glands, culture with calcitriol (10 210 to 10 27 M) for 24 h produced a dose-depen- dent inhibitory effect on the progression of Cells into the Cell cycle and into apoptosis. When glands from patients with 2°HPT were cultured for 24 h, only high calcitriol concentra- tions (10 27 M) inhibited the progression through the Cell cycle and the induction of apoptosis. In Parathyroid adenomas (1°HPT), even a high concentration of calcitriol (10 27 M) had no significant effect on the Cell cycle or apoptosis. The present study shows that in vitro, calcitriol inhibits in a dose-dependent manner in normal Parathyroid glands both Parathyroid Cell proliferation and apoptosis. However, in secondary hyperpla- sia, only high concentrations of calcitriol inhibited Cell prolif- eration and apoptosis. In 1°HPT, even high concentrations of calcitriol had no effect. Because calcitriol simultaneously in- hibits both Cell proliferation and apoptosis, a reduction in the Parathyroid gland mass may not occur as a direct effect of calcitriol treatment.
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The in vitro effect of calcitriol on Parathyroid Cell proliferation and apoptosis.
Journal of the American Society of Nephrology : JASN, 2000Co-Authors: Antonio Canalejo, Yolanda Almaden, Blanca Ramos, Arnold J. Felsenfeld, Jose Maria Campistol, Jose C. Gomez-villamandos, Vanessa Torregrosa, Mariano RodriguezAbstract:Calcitriol treatment is used to reduce Parathyroid hormone levels in azotemic patients with secondary hyperParathyroidism (HPT). Whether long-term calcitriol administration reduces Parathyroid gland size in patients with severe secondary hyperParathyroidism is not clear. The aim of the study was to evaluate in vitro the effect of calcitriol on Parathyroid Cell proliferation and apoptosis in normal Parathyroid glands and in adenomatous and hyperplastic human Parathyroid glands. Freshly harvested Parathyroid glands from normal dogs and hyperplastic and adenomatous glands from patients with secondary (2 degrees) and primary (1 degree) HPT undergoing Parathyroidectomy were studied. Flow cytometry was used to quantify the Cell cycle and apoptosis of Parathyroid Cells. Apoptosis was also evaluated by DNA electrophoresis and light and electron microscopy. In normal dog Parathyroid glands, culture with calcitriol (10(-10) to 10(-7) M) for 24 h produced a dose-dependent inhibitory effect on the progression of Cells into the Cell cycle and into apoptosis. When glands from patients with 2 degrees HPT were cultured for 24 h, only high calcitriol concentrations (10(-7) M) inhibited the progression through the Cell cycle and the induction of apoptosis. In Parathyroid adenomas (1 degrees HPT), even a high concentration of calcitriol (10(-7) M) had no significant effect on the Cell cycle or apoptosis. The present study shows that in vitro, calcitriol inhibits in a dose-dependent manner in normal Parathyroid glands both Parathyroid Cell proliferation and apoptosis. However, in secondary hyperplasia, only high concentrations of calcitriol inhibited Cell proliferation and apoptosis. In 1 degree HPT, even high concentrations of calcitriol had no effect. Because calcitriol simultaneously inhibits both Cell proliferation and apoptosis, a reduction in the Parathyroid gland mass may not occur as a direct effect of calcitriol treatment.
Tally Navehmany - One of the best experts on this subject based on the ideXlab platform.
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Parathyroid Cell resistance to fibroblast growth factor 23 in secondary hyperParathyroidism of chronic kidney disease
Kidney International, 2010Co-Authors: Hillel Galitzer, Justin Silver, Iddo Z Bendov, Tally NavehmanyAbstract: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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rna protein binding and post transcriptional regulation of Parathyroid hormone gene expression by calcium and phosphate
Journal of Biological Chemistry, 1998Co-Authors: Eli Moallem, Justin Silver, Rachel Kilav, Tally NavehmanyAbstract:Abstract Parathyroid hormone (PTH) regulates serum calcium and phosphate levels, which, in turn, regulate PTH secretion and mRNA levels. PTH mRNA levels are markedly increased in rats fed low calcium diets and decreased after low phosphate diets, and this effect is post-transcriptional. Protein-PTH mRNA binding studies, with Parathyroid cytosolic proteins, showed three protein-RNA bands. This binding was to the 3′-untranslated region (UTR) of the PTH mRNA and was dependent upon the terminal 60 nucleotides. Parathyroid proteins from hypocalcemic rats showed increased binding, and proteins from hypophosphatemic rats decreased binding, correlating with PTH mRNA levels. There is no Parathyroid Cell line; however, a functional role was provided by an in vitro degradation assay. Parathyroid proteins from control rats incubated with a PTH mRNA probe led to an intact transcript for 40 min; the transcript was intact with hypocalcemic proteins for 180 min and with hypophosphatemic proteins only for 5 min. A PTH mRNA probe without the 3′-UTR, or just the terminal 60 nucleotides, incubated with hypophosphatemic proteins, showed no degradation at all, indicating that the sequences in the 3′-UTR determine PTH mRNA degradation. Hypocalcemia and hypophosphatemia regulate PTH gene expression post-transcriptionally. This correlates with binding of proteins to the PTH mRNA 3′-UTR, which determines its stability.
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Parathyroid Cell proliferation in normal and chronic renal failure rats the effects of calcium phosphate and vitamin d
Journal of Clinical Investigation, 1995Co-Authors: Tally Navehmany, R Rahamimov, Nelly Livni, Justin SilverAbstract:Abstract Secondary hyperParathyroidism is characterized by an increase in Parathyroid (PT) Cell number, and Parathyroid hormone (PTH) synthesis and secretion. It is still unknown as to what stimuli regulate PT Cell proliferation and how they do this. We have studied rats with dietary-induced secondary hyper- and hypoParathyroidism, rats given 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and rats after 5/6 nephrectomy for the presence of PT Cell proliferation and apoptosis. PT Cell proliferation has been measured by staining for proliferating Cell nuclear antigen (PCNA) and apoptosis by in situ detection of nuclear DNA fragmentation and correlated with serum biochemistry and PTH mRNA levels. A low calcium diet led to increased levels of PTH mRNA and a 10-fold increase in PT Cell proliferation. A low phosphate diet led to decreased levels of PTH mRNA and the complete absence of PT Cell proliferation. 1,25 (OH)2D3 (25 pmol/d x 3) led to a decrease in PTH mRNA levels and unlike the hypophosphatemic rats there was no decrease in Cell proliferation. There were no Cells undergoing apoptosis in any of the experimental conditions. The secondary hyperParathyroidism of 5/6 nephrectomized rats was characterized by an increase in PTH mRNA levels and PT Cell proliferation which were both markedly decreased by a low phosphate diet. The number of PCNA positive Cells was increased by a high phosphate diet. Therefore hypocalcemia, hyperphosphatemia and uremia lead to PT Cell proliferation, and hypophosphatemia completely abolishes this effect. Injected 1,25 (OH)2D3 had no effect. These findings emphasize the importance of a normal phosphate and calcium in the prevention of PT Cell hyperplasia.
Tally Naveh-many - One of the best experts on this subject based on the ideXlab platform.
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Parathyroid Cell Proliferation in Secondary HyperParathyroidism of Chronic Kidney Disease.
International journal of molecular sciences, 2020Co-Authors: Tally Naveh-many, Oded VolovelskyAbstract: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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Post-transcriptional Regulation of Parathyroid Hormone Gene Expression in Health and Disease
Post-transcriptional Mechanisms in Endocrine Regulation, 2016Co-Authors: Tally Naveh-manyAbstract:Parathyroid hormone (PTH) determines mineral metabolism and bone strength. Changes in serum calcium are sensed by the Parathyroid calcium receptor. Secondary hyperParathyroidism (SHP) due to chronic hypocalcemia or chronic kidney disease (CKD) are characterized by increased serum PTH and PTH mRNA levels and Parathyroid Cell proliferation. The increase in PTH gene expression by either dietary induced hypocalcemia or CKD is post-transcriptional and mediated by the differential binding of trans acting proteins to a defined cis element in the PTH mRNA 3′-untranslated region (UTR). These protein-PTH mRNA interactions are orchestrated by the peptidylprolyl isomerase Pin1. Using Parathyroid specific Dicer1 knock-out (PT-Dicer−/−) mice that have reduced micro-RNA (miRNA) expression specifically in their Parathyroids, we showed that miRNA maturation is essential for the increased PTH secretion after both short-term and chronic hypocalcemia in vivo and in vitro, as well as for the SHP of CKD. This chapter discusses the molecular mechanisms that regulate PTH gene expression thereby determining serum PTH levels and mineral metabolism.
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Phosphorylation of Ribosomal Protein S6 Mediates Mammalian Target of Rapamycin Complex 1–Induced Parathyroid Cell Proliferation in Secondary HyperParathyroidism
Journal of the American Society of Nephrology : JASN, 2015Co-Authors: Oded Volovelsky, Justin Silver, Gili Cohen, Ariel Kenig, Gilad Wasserman, Avigail Dreazen, Oded Meyuhas, Tally Naveh-manyAbstract: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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Regulation of Parathyroid Cell proliferation.
Current opinion in nephrology and hypertension, 1997Co-Authors: Justin Silver, Shai Bar Sela, Tally Naveh-manyAbstract:The Parathyroid normally has very few Cells in mitosis but it retains the potential to proliferate. In-vivo studies in rats have demonstrated that hypocalcaemia and high serum phosphate both lead to an increase in the number of proliferating Cells, which is relevant to the increased Parathyroid Cell proliferation in chronic renal failure. Hypophosphataemia and 1,25(OH)2D3 decrease Parathyroid Cell proliferation. Genetic factors have been defined for multiple endocrine neoplasia which includes Parathyroid Cell hyperplasia, and in some Parathyroid adenomas there are genetic rearrangements.
Yolanda Almaden - One of the best experts on this subject based on the ideXlab platform.
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Engineering Parathyroid Cells to treat secondary hyperParathyroidism
Kidney international, 2009Co-Authors: Mariano Rodriguez, Julio M. Martínez-moreno, Yolanda AlmadenAbstract:Kanai et al. used antisense technology to reduce excessive PTH production. The authors have overcome technical difficulties to demonstrate that, by strategies of RNA interference, a steady reduction of PTH secretion can be induced in cultured Parathyroid-Cell spheroids and in athymic nude mice with hyperplastic Parathyroid Cells transplanted from patients with secondary hyperParathyroidism.
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Regulation of Parathyroid function in chronic renal failure
Journal of Bone and Mineral Metabolism, 2006Co-Authors: Mariano Rodriguez, Sagrario Cañadillas, Ignacio Lopez, Escolástico Aguilera-tejero, Yolanda AlmadenAbstract:This review summarizes the factors involved in the development of hyperParathyroidism secondary (2nd-HPTH) to chronic kidney disease (CKD). Calcium and calcitriol act on their respective specific Parathyroid Cell receptors to inhibit Parathyroid function. As well as the well-known effect of calcium and calcitriol on Parathyroid Cell function, there is experimental work that demonstrates that phosphate, changes in pH, PTHrP, estrogens, and some cytokines also have an effect on PTH secretion. These factors are relevant in patients with chronic kidney disease. However, low calcium, vitamin D deficiency, and an accumulation of phosphate due to the decrease in renal function are the main pathogenic factors involved in the pathogenesis of 2nd-HPTH in CKD patients.
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Effects of uremic ultrafiltrate on the regulation of the Parathyroid Cell cycle by calcitriol
Kidney international, 2003Co-Authors: Antonio Canalejo, Yolanda Almaden, Rita De Smet, Griet Glorieux, Bartolome Garfia, Fernando Luque, Raymond Vanholder, Mariano RodriguezAbstract:Effects of uremic ultrafiltrate on the regulation of the Parathyroid Cell cycle by calcitriol. Background Calcitriol (CTR) is used in the treatment of hyperParathyroidism secondary to renal failure because it decreases Parathyroid hormone (PTH) synthesis and Parathyroid Cell proliferation. Previous studies in tissues other than Parathyroids have demonstrated that uremic factors affect the action of CTR on the target Cells. We questioned whether the uremic milieu interferes with the inhibition of Parathyroid Cell proliferation by CTR. Methods Studies were performed in vitro using freshly excised normal dog Parathyroid tissue incubated for 24 hours with and without CTR and in the presence of either total uremic ultrafiltrate (UUF) from uremic patients or high-pressure liquid chromatography (HPLC)-derived fractions (hydrophilic compounds eluting early and hydrophobic compounds eluting late) of this UUF (F1 to F4). Parathyroid Cell proliferation was assessed by flow cytometry. Results The addition of CTR 10 -8 and 10 -7 mol/L to Parathyroid tissue produced an inhibition of the proliferation that was prevented in the presence of UUF. In a medium containing CTR 10 -8 mol/L, the addition of F1, F2 and F3, but not F4, prevented the CTR-induced inhibition of Parathyroid Cell proliferation. With CTR 10 -7 mol/L, the inhibition of proliferation was observed even in the presence of F1, F2 and also F4, but was prevented by F3. Uric acid (7 mg/dL), indoxyl sulfate (5 mg/dL) and p-cresol (1.4 mg/dL), which coeluted with F1, F2 and F4, respectively, did not interfere with the inhibitory action of CTR 10 -7 mol/L; however, the addition of phenol (0.14 mg/dL), which coeluted with F3, prevented the CTR-induced inhibition of Parathyroid Cell proliferation. Conclusions The presence of uremic toxins prevents the inhibition of Parathyroid Cell proliferation induced by calcitriol.
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The in vitro effect of calcitriol on Parathyroid Cell proliferation and apoptosis.
Journal of The American Society of Nephrology, 2000Co-Authors: Antonio Canalejo, Yolanda Almaden, Blanca Ramos, Arnold J. Felsenfeld, Jose Maria Campistol, Jose C. Gomez-villamandos, Vanessa Torregrosa, Mariano RodriguezAbstract:Calcitriol treatment is used to reduce Parathyroid hormone levels in azotemic patients with secondary hyperpara- thyroidism (HPT). Whether long-term calcitriol administration reduces Parathyroid gland size in patients with severe second- ary hyperParathyroidism is not clear. The aim of the study was to evaluate in vitro the effect of calcitriol on Parathyroid Cell proliferation and apoptosis in normal Parathyroid glands and in adenomatous and hyperplastic human Parathyroid glands. Freshly harvested Parathyroid glands from normal dogs and hyperplastic and adenomatous glands from patients with sec- ondary (2°) and primary (1°) HPT undergoing Parathyroidec- tomy were studied. Flow cytometry was used to quantify the Cell cycle and apoptosis of Parathyroid Cells. Apoptosis was also evaluated by DNA electrophoresis and light and electron microscopy. In normal dog Parathyroid glands, culture with calcitriol (10 210 to 10 27 M) for 24 h produced a dose-depen- dent inhibitory effect on the progression of Cells into the Cell cycle and into apoptosis. When glands from patients with 2°HPT were cultured for 24 h, only high calcitriol concentra- tions (10 27 M) inhibited the progression through the Cell cycle and the induction of apoptosis. In Parathyroid adenomas (1°HPT), even a high concentration of calcitriol (10 27 M) had no significant effect on the Cell cycle or apoptosis. The present study shows that in vitro, calcitriol inhibits in a dose-dependent manner in normal Parathyroid glands both Parathyroid Cell proliferation and apoptosis. However, in secondary hyperpla- sia, only high concentrations of calcitriol inhibited Cell prolif- eration and apoptosis. In 1°HPT, even high concentrations of calcitriol had no effect. Because calcitriol simultaneously in- hibits both Cell proliferation and apoptosis, a reduction in the Parathyroid gland mass may not occur as a direct effect of calcitriol treatment.
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The in vitro effect of calcitriol on Parathyroid Cell proliferation and apoptosis.
Journal of the American Society of Nephrology : JASN, 2000Co-Authors: Antonio Canalejo, Yolanda Almaden, Blanca Ramos, Arnold J. Felsenfeld, Jose Maria Campistol, Jose C. Gomez-villamandos, Vanessa Torregrosa, Mariano RodriguezAbstract:Calcitriol treatment is used to reduce Parathyroid hormone levels in azotemic patients with secondary hyperParathyroidism (HPT). Whether long-term calcitriol administration reduces Parathyroid gland size in patients with severe secondary hyperParathyroidism is not clear. The aim of the study was to evaluate in vitro the effect of calcitriol on Parathyroid Cell proliferation and apoptosis in normal Parathyroid glands and in adenomatous and hyperplastic human Parathyroid glands. Freshly harvested Parathyroid glands from normal dogs and hyperplastic and adenomatous glands from patients with secondary (2 degrees) and primary (1 degree) HPT undergoing Parathyroidectomy were studied. Flow cytometry was used to quantify the Cell cycle and apoptosis of Parathyroid Cells. Apoptosis was also evaluated by DNA electrophoresis and light and electron microscopy. In normal dog Parathyroid glands, culture with calcitriol (10(-10) to 10(-7) M) for 24 h produced a dose-dependent inhibitory effect on the progression of Cells into the Cell cycle and into apoptosis. When glands from patients with 2 degrees HPT were cultured for 24 h, only high calcitriol concentrations (10(-7) M) inhibited the progression through the Cell cycle and the induction of apoptosis. In Parathyroid adenomas (1 degrees HPT), even a high concentration of calcitriol (10(-7) M) had no significant effect on the Cell cycle or apoptosis. The present study shows that in vitro, calcitriol inhibits in a dose-dependent manner in normal Parathyroid glands both Parathyroid Cell proliferation and apoptosis. However, in secondary hyperplasia, only high concentrations of calcitriol inhibited Cell proliferation and apoptosis. In 1 degree HPT, even high concentrations of calcitriol had no effect. Because calcitriol simultaneously inhibits both Cell proliferation and apoptosis, a reduction in the Parathyroid gland mass may not occur as a direct effect of calcitriol treatment.
