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Genes regulated by high calcium medium in parathyroid tissue explants from patients with primary hyperparathyroidism

ABSTRACT: To investigate genes modulated in the parathyroid glands by calcium, expression levels of mRNA for all genes expressed in parathyroid tissue explants (PTEs) obtained from patients with primary hyperparathyroidism (I-HPT) were analyzed by oligo-DNA microarray. PTEs obtained from 4 patients with I-HPT were precultured in normocalcemic medium (Ca++ 1.0-1.1 mM) for 7 days and then cultured in hypocalcemic medium (Ca++ 0.60 mM) or hypercalcemic (Ca++ 1.60 mM) medium for an additional 7 days. As expected, expression levels of mRNA for PTH and chromogranin A were decreased to less than 50%　in hypercalcemic medium. Furthermore, oligo-DNA microarray analyses followed by GeneSpring GX analyses revealed that 7 genes were up-regulated by more than 2-fold and more than 30 genes were down-regulated by more than 1/2 in PTEs obtained from patients with I-HPT. Interestingly, 9 of these genes (up-regulated genes: chemokine ligand 8[CCL8], multiple C2 domain and transmembrane region protein 1 [MCTP1]; down-regulated genes: matrix metallopeptidase-9 [MMP9], B-box and SPRY domain-containing protein [BSPRY], nitric oxide synthase 2A [NOS2A], parathyroid hormone [PTH], cartilage acidic protein 1 [CRTAC1], chromogranin A [CHGA], and fibrin 1 [FBLN1]) were involved in calcium metabolism or calcium-signaling pathways in the parathyroid tissue. Unexpectedly, however, the expression level of mRNA for alpha-klotho was variable, and it was not constantly decreased in hypercalcemic medium under the present experimental conditions. Although it was not possible to use normal parathyroid tissue, this is the first reported study to have investigated the expression levels of mRNA for all genes in human parathyroid adenomas that are modulated by high calcium concentration in organ culture.

ORGANISM(S): Homo sapiens

PROVIDER: GSE18689 | GEO | 2009/10/23

SECONDARY ACCESSION(S): PRJNA121569

REPOSITORIES: GEO

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Project description:The pathogenesis of primary hyperparathyroidism (I-HPT) and secondary hyperparathyroidism (II-PTH) remains to be elucidated. To characterize their pathophysiology, we investigated the effects of calcium and phosphate on cell proliferation and PTH release in an organ culture of parathyroid tissues. Dissected parathyroid tissues obtained from patients with I-HPT (adenoma) or II-PTH (nodular hyperplasia) were precultured on a collagen-coated membrane for 1-4 week. After exchanging the medium for one containing various concentrations of phosphate, PTH release and [3H]thymidine incorporation were studied. In contrast to dispersed parathyroid cells cultured in a monolayer, calcium decreased PTH release in a concentration-dependent manner in parathyroid tissues. Furthermore, when parathyroid tissues obtained from II-PTH were precultured for 1-4 weeks, PTH release and parathyroid cell proliferation were significantly increased in high-phosphate medium. These phosphate effects were also observed to a lesser extent in parathyroid tissues obtained from I-HPT, but there was no significant difference between I-HPT and II-HPT. Microarray analyses revealed that mRNA levels of PTH, CaSR, and VDR were well preserved, and several growth factors (e.g. TGF-beta1-induced protein) were abundantly expressed in II-PTH. Using organ cultures of hyperparathyroid tissues, in which PTH release and CaSR are well preserved for a prolonged period, we have demonstrated that phosphate stimulates parathyroid cell proliferation not only in II-PTH but also in I-HPT. Although the mechanism responsible for phosphate-induced cell proliferation remains to be elucidated, our in vitro findings suggest that both parathyroid tissues preserve to some extent a physiological response system to hyperphosphatemia as observed in normal parathyroid cells. These data will be published in Journal of Bone & Mineral Metabolism. Experiment Overall Design: Two conditioned experimets, low vs. high phosphate medium, cultured for 1 and 4 days

Project description:The pathogenesis of primary hyperparathyroidism (I-HPT) and secondary hyperparathyroidism (II-PTH) remains to be elucidated. To characterize their pathophysiology, we investigated the effects of calcium and phosphate on cell proliferation and PTH release in an organ culture of parathyroid tissues. Dissected parathyroid tissues obtained from patients with I-HPT (adenoma) or II-PTH (nodular hyperplasia) were precultured on a collagen-coated membrane for 1-4 week. After exchanging the medium for one containing various concentrations of phosphate, PTH release and [3H]thymidine incorporation were studied. In contrast to dispersed parathyroid cells cultured in a monolayer, calcium decreased PTH release in a concentration-dependent manner in parathyroid tissues. Furthermore, when parathyroid tissues obtained from II-PTH were precultured for 1-4 weeks, PTH release and parathyroid cell proliferation were significantly increased in high-phosphate medium. These phosphate effects were also observed to a lesser extent in parathyroid tissues obtained from I-HPT, but there was no significant difference between I-HPT and II-HPT. Microarray analyses revealed that mRNA levels of PTH, CaSR, and VDR were well preserved, and several growth factors (e.g. TGF-beta1-induced protein) were abundantly expressed in II-PTH. Using organ cultures of hyperparathyroid tissues, in which PTH release and CaSR are well preserved for a prolonged period, we have demonstrated that phosphate stimulates parathyroid cell proliferation not only in II-PTH but also in I-HPT. Although the mechanism responsible for phosphate-induced cell proliferation remains to be elucidated, our in vitro findings suggest that both parathyroid tissues preserve to some extent a physiological response system to hyperphosphatemia as observed in normal parathyroid cells. These data will be published in Journal of Bone & Mineral Metabolism. Keywords: Organ culture experiments, dultured in low vs.high phosphate medium

Project description:This a model from the article: A mathematical model of parathyroid hormone response to acute changes in plasma ionized calcium concentration in humans. Shrestha RP, Hollot CV, Chipkin SR, Schmitt CP, Chait Y. Math Biosci.2010 Jul;226(1):46-57. 20406649, Abstract: A complex bio-mechanism, commonly referred to as calcium homeostasis, regulates plasma ionized calcium (Ca(2+)) concentration in the human body within a narrow range which is crucial for maintaining normal physiology and metabolism. Taking a step towards creating a complete mathematical model of calcium homeostasis, we focus on the short-term dynamics of calcium homeostasis and consider the response of the parathyroid glands to acute changes in plasma Ca(2+) concentration. We review available models, discuss their limitations, then present a two-pool, linear, time-varying model to describe the dynamics of this calcium homeostasis subsystem, the Ca-PTH axis. We propose that plasma PTH concentration and plasma Ca(2+) concentration bear an asymmetric reverse sigmoid relation. The parameters of our model are successfully estimated based on clinical data corresponding to three healthy subjects that have undergone induced hypocalcemic clamp tests. In the first validation of this kind, with parameters estimated separately for each subject we test the model's ability to predict the same subject's induced hypercalcemic clamp test responses. Our results demonstrate that a two-pool, linear, time-varying model with an asymmetric reverse sigmoid relation characterizes the short-term dynamics of the Ca-PTH axis. The model corresponds to hypercalcemic clamp test explained in the paper and parameter values used in the model are that of "subject 1". In order to obtain the plots corresponding to "subject 2" and "subject 3" the following parameters to be changed: lambda_1, lambda_2, m1, m2, R, beta, x1_n, x2_n, x2_min, x2_max, t0, Ca0, Ca1 and alpha. parameter Subject 1 Subject 2 Subject 3 lambda_1 0.0125 0.0122 0.0269 lambda_2 0.5595 0.4642 0.4935 m1 112.5200 150.0000 90.8570 m2 15.0000 15.0000 15.0000 R 1.2162 1.1627 1.1889 beta 10e+06 10e+06 10e+06 x1_n 490.7800 452.8200 298.8200 x2_n 6.6290 9.5894 5.4600 x2_min 0.6697 1.4813 0.8287 x2_max 14.0430 17.8710 15.1990 Ca0 1.2200 1.2513 1.2480 Ca1 0.2624 0.2267 0.2132 t0 575 575 575 alpha 0.0569 0.0563 0.0421 This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:This a model from the article: A mathematical model of parathyroid hormone response to acute changes in plasma ionized calcium concentration in humans. Shrestha RP, Hollot CV, Chipkin SR, Schmitt CP, Chait Y. Math Biosci.2010 Jul;226(1):46-57. 20406649, Abstract: A complex bio-mechanism, commonly referred to as calcium homeostasis, regulates plasma ionized calcium (Ca(2+)) concentration in the human body within a narrow range which is crucial for maintaining normal physiology and metabolism. Taking a step towards creating a complete mathematical model of calcium homeostasis, we focus on the short-term dynamics of calcium homeostasis and consider the response of the parathyroid glands to acute changes in plasma Ca(2+) concentration. We review available models, discuss their limitations, then present a two-pool, linear, time-varying model to describe the dynamics of this calcium homeostasis subsystem, the Ca-PTH axis. We propose that plasma PTH concentration and plasma Ca(2+) concentration bear an asymmetric reverse sigmoid relation. The parameters of our model are successfully estimated based on clinical data corresponding to three healthy subjects that have undergone induced hypocalcemic clamp tests. In the first validation of this kind, with parameters estimated separately for each subject we test the model's ability to predict the same subject's induced hypercalcemic clamp test responses. Our results demonstrate that a two-pool, linear, time-varying model with an asymmetric reverse sigmoid relation characterizes the short-term dynamics of the Ca-PTH axis. The model corresponds to hypocalcemic clamp test explained in the paper and parameter values used in the model are that of "subject 1". In order to obtain the plots corresponding to "subject 2" and "subject 3" the following parameters to be changed: lambda_1, lambda_2, m1, m2, R, beta, x1_n, x2_n, x2_min, x2_max, Ca0, Ca1, t0 and alpha. parameter Subject 1 Subject 2 Subject 3 lambda_1 0.0125 0.0122 0.0269 lambda_2 0.5595 0.4642 0.4935 m1 112.5200 150.0000 90.8570 m2 15.0000 15.0000 15.0000 R 1.2162 1.1627 1.1889 beta 10e+06 10e+06 10e+06 x1_n 490.7800 452.8200 298.8200 x2_n 6.6290 9.5894 5.4600 x2_min 0.6697 1.4813 0.8287 x2_max 14.0430 17.8710 15.1990 Ca0 1.2550 1.2369 1.2475 Ca1 0.1817 0.2211 0.1985 t0 575 577 575 alpha 0.0442 0.0488 0.0472 This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:<p>Maintaining calcium levels within a narrow normal range is of critical importance for numerous different cellular functions. One of the most important regulators of blood calcium levels is parathyroid hormone (PTH), which mediates its actions through the PTH/PTHrP receptor, a Gαs-coupled receptor. Few inherited disorders are characterized by diminished blood calcium levels and elevated blood phosphate levels; some of these disorders are caused by too little PTH synthesis and/or secretion (hypoparathyroidism, HP), while others are caused by resistance towards PTH (pseudohypoparathyroidism, PHP). Only few of the inherited forms of HP (<10%) have been defined at the molecular level. In contrast, genetic mutations have been identified for several inherited forms of PHP. For example, PHP type Ia (PHP-Ia) is caused by maternally inherited mutations in those GNAS exons that encode Gαs, while autosomal dominant PHP type Ib (AD-PHP-Ib) is caused by maternal inherited deletions within or up-stream of GNAS, which are associated with abnormal GNAS methylation. However, a large number of patients with PTH-resistance and thus hypocalcemia show GNAS methylation changes, but their underlying genetic defects have not yet been defined at the DNA level. These "sporadic" patients may be affected by an autosomal recessive form of PHP-Ib (AR-PHP-Ib), which is most likely not linked to the GNAS locus. In our studies, we propose to search through exome sequence analyses for novel genetic mutations responsible for novel autosomal dominant forms of HP that are not caused by mutations in the known disease-causing genes; some of these families are large enough to perform genetic linkage studies. We furthermore propose to search for the genetic mutation(s) responsible for the autosomal recessive variant of PHP-Ib through the analysis of whole exome sequences; for these studies we focus particularly on patients, whose parents are likely to be consanguineous. The proposed efforts are expected to lead to the identification of novel genes that are involved in parathyroid development and function (HP) and genes that are involved in the establishment or maintenance of GNAS methylation (AR-PHP-Ib). </p>

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Genes regulated by high calcium medium in parathyroid tissue explants from patients with primary hyperparathyroidism

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