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Parathyroid hormone secretion by multiple distinct cell populations, a time dynamic mathematical model

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Physiological Reports

Wiley Periodicals, Inc.

Calcium, hysteresis, parathyroid hormone, simulation

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      Abstract

      The acute response of parathyroid hormone to perturbations in serum ionized calcium ([Ca 2+]) is physiologically complex, and poorly understood. The literature provides numerous observations of quantitative and qualitative descriptions of parathyroid hormone (PTH) dynamics. We present a physiologically based mathematical model of PTH secretion constructed from mechanisms suggested in the literature, and validated against complex [Ca 2+] clamping protocols from human data. The model is based on two assumptions. The first is that secretion is a fraction of cellular reserves, with the fraction being determined by the kinetics of [Ca 2+] with its receptor. The second is that there are multiple distinct populations of parathyroid cells, with different secretory parameters. The steady state and transient PTH secretion responses of the model are in agreement with human experimental PTH responses to different hypocalcemia and hypercalcemia stimuli. This mathematical model suggests that a population of secreting cells is responsible for the PTH secretory dynamics observed experimentally.

      Abstract

      We present a physiologically based mathematical model of parathyroid hormone (PTH) secretion constructed from mechanisms suggested in the literature, and validated against complex [Ca2+] clamping protocols from human data. The steady state and transient PTH secretion responses of the model are in agreement with human experimental PTH responses to different hypo and hypercalcemia stimuli. This mathematical model suggests that a population of secreting cells is responsible for the PTH secretory dynamics observed experimentally.

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      Most cited references 37

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      The parathyroid is a target organ for FGF23 in rats.

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

        Bone biology is physiologically complex and intimately linked to calcium homeostasis. The literature provides a wealth of qualitative and/or quantitative descriptions of cellular mechanisms, bone dynamics, associated organ dynamics, related disease sequela, and results of therapeutic interventions. We present a physiologically based mathematical model of integrated calcium homeostasis and bone biology constructed from literature data. The model includes relevant cellular aspects with major controlling mechanisms for bone remodeling and calcium homeostasis and appropriately describes a broad range of clinical and therapeutic conditions. These include changes in plasma parathyroid hormone (PTH), calcitriol, calcium and phosphate (PO4), and bone-remodeling markers as manifested by hypoparathyroidism and hyperparathyroidism, renal insufficiency, daily PTH 1-34 administration, and receptor activator of NF-kappaB ligand (RANKL) inhibition. This model highlights the utility of systems approaches to physiologic modeling in the bone field. The presented bone and calcium homeostasis model provides an integrated mathematical construct to conduct hypothesis testing of influential system aspects, to visualize elements of this complex endocrine system, and to continue to build upon iteratively with the results of ongoing scientific research. Copyright (c) 2009 Elsevier Inc. All rights reserved.
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          Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat.

          In vitro 1,25-dihydroxycholecalciferol (1,25(OH)2D3) decreased levels of preproparathyroid(preproPTH) hormone mRNA. We have now pursued these studies in vivo in the rat. Rats were administered vitamin D metabolites i.p. and the levels of preproPTH mRNA were determined in excised parathyroid-thyroid glands by blot hybridization. PreproPTH mRNA levels were less than 4% of basal at 48 h after 100 pmol 1,25(OH)2D3, with no increase in serum calcium. Gel blots showed that 1,25(OH)2D3 decreased preproPTH mRNA levels without any change in its size (833 basepair). Microdissected parathyroids after 1,25(OH)2D3 (100 pmol) showed mRNA levels for preproPTH were 40 +/- 8% of controls, but for beta-actin were 100% of controls. The relative potencies of vitamin D metabolites were: 1,25(OH)2D3 greater than 24,25(OH)2D3 greater than 25(OH)D3 greater than vitamin D3. In vitro nuclear transcription showed that 1,25(OH)2D3-treated (100 pmol) rats' PTH transcription was 10% of control, while beta-actin was 100%. These results show that 1,25(OH)2D3 regulates PTH gene transcription. PTH stimulates 1,25(OH)2D3 synthesis, which then inhibits PTH synthesis, thus completing an endocrinological feedback loop.
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            Author and article information

            Affiliations
            [1 ]Department of Physiology, Center for Computational Medicine, University of Mississippi Medical Center, Jackson, 39216, Mississippi
            Author notes
            CorrespondenceRobert L. Hester, Department of Physiology,University of Mississippi Medical Center,2500 N State Street, Jackson, MS 39216.Tel: 601‐984‐1820Fax: 601‐984‐1817E‐mail: rhester@ 123456umc.edu
            Journal
            Physiol Rep
            Physiol Rep
            physreports
            phy2
            Physiological Reports
            Wiley Periodicals, Inc.
            2051-817X
            1 February 2014
            10 February 2014
            : 2
            : 2
            3966243 phy2231 10.1002/phy2.231
            © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

            This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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