Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1990 Oct;86(4):1313–1319. doi: 10.1172/JCI114840

Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat.

T Naveh-Many 1, J Silver 1
PMCID: PMC296864  PMID: 2212016

Abstract

In vivo in the rat 1,25(OH)2D3 decreases and a low calcium increases PTH mRNA levels. We now report the effect of 3 and 8 wk of changes in dietary vitamin D and calcium on PTH mRNA levels. PTH mRNA levels were increased by 3 wk of calcium deficiency (five times), a vitamin D-deficient diet (two times), and combined deficiency (10 times), but not changed by high calcium. Vitamin D-deficient-diet rats' PTH mRNA did not decrease after a single large dose of 1,25(OH)2D3, but did decrease partially after repeated daily doses of 1,25(OH)2D3. Rats after a vitamin D-, calcium-deficient (-D-Ca) diet did not respond to changes in serum calcium at 1 h. Flow cytometry of isolated cells from parathyroid-thyroid tissue separated the smaller parathyroid from the larger thyroid cells and allowed an analysis of parathyroid cell number. In normal vitamin D/normal calcium (NDNCa) rats the parathyroid cells were 24.7 +/- 3.4% (n = 6) of the total cell number, whereas in -D-Ca rats they were 41.8 +/- 6.6% (n = 6) (P less than 0.05). That is, -D-Ca rats had 1.7 times the number of cells, whereas they had 10 times the amount of PTH mRNA, indicating the major contribution (6 times) of increased PTH gene expression per cell. Moreover, a calcium-deficient, more so than a vitamin D-deficient diet, amplifies the expression of the PTH gene, and vitamin D is necessary for an intact response of PTH mRNA to 1,25(OH)2D3 or calcium.

Full text

PDF
1313

Images in this article

1314Image
on p.1314
1317Image
on p.1317

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baker L. R., Abrams L., Roe C. J., Faugere M. C., Fanti P., Subayti Y., Malluche H. H. 1,25(OH)2D3 administration in moderate renal failure: a prospective double-blind trial. Kidney Int. 1989 Feb;35(2):661–669. doi: 10.1038/ki.1989.36. [DOI] [PubMed] [Google Scholar]
  2. Brookman J. J., Farrow S. M., Nicholson L., O'Riordan J. L., Hendy G. N. Regulation by calcium of parathyroid hormone mRNA in cultured parathyroid tissue. J Bone Miner Res. 1986 Dec;1(6):529–537. doi: 10.1002/jbmr.5650010607. [DOI] [PubMed] [Google Scholar]
  3. Brown A. J., Dusso A., Lopez-Hilker S., Lewis-Finch J., Grooms P., Slatopolsky E. 1,25-(OH)2D receptors are decreased in parathyroid glands from chronically uremic dogs. Kidney Int. 1989 Jan;35(1):19–23. doi: 10.1038/ki.1989.3. [DOI] [PubMed] [Google Scholar]
  4. Cote G. J., Rogers D. G., Huang E. S., Gagel R. F. The effect of 1,25-dihydroxyvitamin D3 treatment on calcitonin and calcitonin gene-related peptide mRNA levels in cultured human thyroid C-cells. Biochem Biophys Res Commun. 1987 Nov 30;149(1):239–243. doi: 10.1016/0006-291x(87)91630-5. [DOI] [PubMed] [Google Scholar]
  5. Hendy G. N., Stotland M. A., Grunbaum D., Fraher L. J., Loveridge N., Goltzman D. Characteristics of secondary hyperparathyroidism in vitamin D-deficient dogs. Am J Physiol. 1989 Jun;256(6 Pt 1):E765–E772. doi: 10.1152/ajpendo.1989.256.6.E765. [DOI] [PubMed] [Google Scholar]
  6. Korkor A. B. Reduced binding of [3H]1,25-dihydroxyvitamin D3 in the parathyroid glands of patients with renal failure. N Engl J Med. 1987 Jun 18;316(25):1573–1577. doi: 10.1056/NEJM198706183162504. [DOI] [PubMed] [Google Scholar]
  7. Lopez-Hilker S., Galceran T., Chan Y. L., Rapp N., Martin K. J., Slatopolsky E. Hypocalcemia may not be essential for the development of secondary hyperparathyroidism in chronic renal failure. J Clin Invest. 1986 Oct;78(4):1097–1102. doi: 10.1172/JCI112666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Matsumoto T., Ikeda K., Yamato H., Morita K., Ezawa I., Fukushima M., Nishii Y., Ogata E. Effect of 24,25-dihydroxyvitamin D3 on 1,25-dihydroxyvitamin D3 metabolism in calcium-deficient rats. Biochem J. 1988 Mar 15;250(3):671–677. doi: 10.1042/bj2500671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. McDonnell D. P., Mangelsdorf D. J., Pike J. W., Haussler M. R., O'Malley B. W. Molecular cloning of complementary DNA encoding the avian receptor for vitamin D. Science. 1987 Mar 6;235(4793):1214–1217. doi: 10.1126/science.3029866. [DOI] [PubMed] [Google Scholar]
  10. Merke J., Hügel U., Zlotkowski A., Szabó A., Bommer J., Mall G., Ritz E. Diminished parathyroid 1,25(OH)2D3 receptors in experimental uremia. Kidney Int. 1987 Sep;32(3):350–353. doi: 10.1038/ki.1987.216. [DOI] [PubMed] [Google Scholar]
  11. Naveh-Many T., Friedlaender M. M., Mayer H., Silver J. Calcium regulates parathyroid hormone messenger ribonucleic acid (mRNA), but not calcitonin mRNA in vivo in the rat. Dominant role of 1,25-dihydroxyvitamin D. Endocrinology. 1989 Jul;125(1):275–280. doi: 10.1210/endo-125-1-275. [DOI] [PubMed] [Google Scholar]
  12. Naveh-Many T., Silver J. Regulation of calcitonin gene transcription by vitamin D metabolites in vivo in the rat. J Clin Invest. 1988 Jan;81(1):270–273. doi: 10.1172/JCI113305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Nordal K. P., Dahl E. Low dose calcitriol versus placebo in patients with predialysis chronic renal failure. J Clin Endocrinol Metab. 1988 Nov;67(5):929–936. doi: 10.1210/jcem-67-5-929. [DOI] [PubMed] [Google Scholar]
  14. Nygren P., Larsson R., Johansson H., Ljunghall S., Rastad J., Akerström G. 1,25(OH)2D3 inhibits hormone secretion and proliferation but not functional dedifferentiation of cultured bovine parathyroid cells. Calcif Tissue Int. 1988 Oct;43(4):213–218. doi: 10.1007/BF02555137. [DOI] [PubMed] [Google Scholar]
  15. Okazaki T., Igarashi T., Kronenberg H. M. 5'-flanking region of the parathyroid hormone gene mediates negative regulation by 1,25-(OH)2 vitamin D3. J Biol Chem. 1988 Feb 15;263(5):2203–2208. [PubMed] [Google Scholar]
  16. Pitts T. O., Piraino B. H., Mitro R., Chen T. C., Segre G. V., Greenberg A., Puschett J. B. Hyperparathyroidism and 1,25-dihydroxyvitamin D deficiency in mild, moderate, and severe renal failure. J Clin Endocrinol Metab. 1988 Nov;67(5):876–881. doi: 10.1210/jcem-67-5-876. [DOI] [PubMed] [Google Scholar]
  17. Ramp W. K., Cooper C. W., Ross A. J., 3rd, Wells S. A., Jr Effects of calcium and cyclic nucleotides on rat calcitonin and parathyroid hormone secretion. Mol Cell Endocrinol. 1979 Jun;14(3):205–215. doi: 10.1016/0303-7207(79)90046-7. [DOI] [PubMed] [Google Scholar]
  18. Russell J., Lettieri D., Sherwood L. M. Direct regulation by calcium of cytoplasmic messenger ribonucleic acid coding for pre-proparathyroid hormone in isolated bovine parathyroid cells. J Clin Invest. 1983 Nov;72(5):1851–1855. doi: 10.1172/JCI111146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Silver J., Naveh-Many T., Mayer H., Schmelzer H. J., Popovtzer M. M. Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest. 1986 Nov;78(5):1296–1301. doi: 10.1172/JCI112714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Silver J., Russell J., Sherwood L. M. Regulation by vitamin D metabolites of messenger ribonucleic acid for preproparathyroid hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4270–4273. doi: 10.1073/pnas.82.12.4270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Slatopolsky E., Weerts C., Thielan J., Horst R., Harter H., Martin K. J. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxy-cholecalciferol in uremic patients. J Clin Invest. 1984 Dec;74(6):2136–2143. doi: 10.1172/JCI111639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Svensson O., Wernerson A., Reinholt F. P. Effect of calcium depletion on the rat parathyroids. Bone Miner. 1988 Jan;3(3):259–269. [PubMed] [Google Scholar]
  23. Szabo A., Merke J., Beier E., Mall G., Ritz E. 1,25(OH)2 vitamin D3 inhibits parathyroid cell proliferation in experimental uremia. Kidney Int. 1989 Apr;35(4):1049–1056. doi: 10.1038/ki.1989.89. [DOI] [PubMed] [Google Scholar]
  24. Wernerson A., Svensson O., Reinholt F. P. Parathyroid cell number and size in hypercalcemic rats: a stereologic study employing modern unbiased estimators. J Bone Miner Res. 1989 Oct;4(5):705–713. doi: 10.1002/jbmr.5650040509. [DOI] [PubMed] [Google Scholar]
  25. Yamamoto M., Igarashi T., Muramatsu M., Fukagawa M., Motokura T., Ogata E. Hypocalcemia increases and hypercalcemia decreases the steady-state level of parathyroid hormone messenger RNA in the rat. J Clin Invest. 1989 Mar;83(3):1053–1056. doi: 10.1172/JCI113946. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES