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. 1996 Jun 1;97(11):2534–2540. doi: 10.1172/JCI118701

Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro.

E Slatopolsky 1, J Finch 1, M Denda 1, C Ritter 1, M Zhong 1, A Dusso 1, P N MacDonald 1, A J Brown 1
PMCID: PMC507339  PMID: 8647946

Abstract

Dietary phosphorus (P) restriction is known to ameliorate secondary hyperparathyroidism in renal failure patients. In early renal failure, this effect may be mediated by an increase in 1,25-(OH)2D3, whereas in advanced renal failure, P restriction can act independent of changes in 1,25-(OH)2D3 and serum ionized calcium (ICa). In this study, we examined the effects of dietary P on serum PTH, PTH mRNA, and parathyroid gland (PTG) hyperplasia in uremic rats. Normal and uremic rats were maintained on a low (0.2%) or high (0.8%) P diet for 2 mo. PTG weight and serum PTH were similar in both groups of normal rats and in uremic rats fed the 0.2% P diet. In contrast, there were significant increases in serum PTH (130 +/- 25 vs. 35 +/- 3.5 pg/ml, P < 0.01), PTG weight (1.80 +/- 0.13 vs. 0.88 +/- 0.06 microg/gram of body weight, P < 0.01), and PTG DNA (1.63 +/- 0.24 vs. 0.94 +/- 0.07 microg DNA/gland, P < 0.01) in the uremic rats fed the 0.8% P diet as compared with uremic rats fed the 0.2% P diet. Serum ICa and 1,25-(OH)2D3 were not altered over this range of dietary P, suggesting a direct effect of P on PTG function. We tested this possibility in organ cultures of rat PTGs. While PTH secretion was acutely (30 min) regulated by medium calcium, the effects of medium P were not evident until 3 h. During a 6-h incubation, PTH accumulation was significantly greater in the 2.8 mM P medium than in the 0.2 mM P medium (1,706 +/- 215 vs. 1,033 +/- 209 pg/microg DNA, P < 0.02); the medium ICa was 1.25 mM in both conditions. Medium P did not alter PTH mRNA in this system, but cycloheximide (10 microg/ml) abolished the effect of P on PTH secretion. Thus, the effect of P is posttranscriptional, affecting PTH at a translational or posttranslational step. Collectively, these in vivo and in vitro results demonstrate a direct action of P on PTG function that is independent of ICa and 1,25-(OH)2D3.

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Selected References

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  1. Aparicio M., Combe C., Lafage M. H., de Precigout V., Potaux L., Bouchet J. L. In advanced renal failure, dietary phosphorus restriction reverses hyperparathyroidism independent of changes in the levels of calcitriol. Nephron. 1993;63(1):122–123. doi: 10.1159/000187162. [DOI] [PubMed] [Google Scholar]
  2. Arnold A., Brown M. F., Ureña P., Gaz R. D., Sarfati E., Drüeke T. B. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest. 1995 May;95(5):2047–2053. doi: 10.1172/JCI117890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arnold A., Kim H. G., Gaz R. D., Eddy R. L., Fukushima Y., Byers M. G., Shows T. B., Kronenberg H. M. Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest. 1989 Jun;83(6):2034–2040. doi: 10.1172/JCI114114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Drake T. G., Albright F., Castleman B. PARATHYROID HYPERPLASIA IN RABBITS PRODUCED BY PARENTERAL PHOSPHATE ADMINISTRATION. J Clin Invest. 1937 Mar;16(2):203–206. doi: 10.1172/JCI100848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Fukuda N., Tanaka H., Tominaga Y., Fukagawa M., Kurokawa K., Seino Y. Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest. 1993 Sep;92(3):1436–1443. doi: 10.1172/JCI116720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hruska K. A., Kopelman R., Rutherford W. E., Klahr S., Slatopolsky E., Greenwalt A., Bascom T., Markham J. Metabolism in immunoreactive parathyroid hormone in the dog. The role of the kidney and the effects of chronic renal disease. J Clin Invest. 1975 Jul;56(1):39–48. doi: 10.1172/JCI108077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Kilav R., Silver J., Naveh-Many T. Parathyroid hormone gene expression in hypophosphatemic rats. J Clin Invest. 1995 Jul;96(1):327–333. doi: 10.1172/JCI118038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Le Pecq J. B., Paoletti C. A new fluorometric method for RNA and DNA determination. Anal Biochem. 1966 Oct;17(1):100–107. doi: 10.1016/0003-2697(66)90012-1. [DOI] [PubMed] [Google Scholar]
  9. Lopez-Hilker S., Dusso A. S., Rapp N. S., Martin K. J., Slatopolsky E. Phosphorus restriction reverses hyperparathyroidism in uremia independent of changes in calcium and calcitriol. Am J Physiol. 1990 Sep;259(3 Pt 2):F432–F437. doi: 10.1152/ajprenal.1990.259.3.F432. [DOI] [PubMed] [Google Scholar]
  10. Lucas P. A., Brown R. C., Woodhead J. S., Coles G. A. 1,25-dihydroxycholecalciferol and parathyroid hormone in advanced chronic renal failure: effects of simultaneous protein and phosphorus restriction. Clin Nephrol. 1986 Jan;25(1):7–10. [PubMed] [Google Scholar]
  11. MacDonald P. N., Ritter C., Brown A. J., Slatopolsky E. Retinoic acid suppresses parathyroid hormone (PTH) secretion and PreproPTH mRNA levels in bovine parathyroid cell culture. J Clin Invest. 1994 Feb;93(2):725–730. doi: 10.1172/JCI117026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. MacGregor R. R., Sarras M. P., Jr, Houle A., Cohn D. V. Primary monolayer cell culture of bovine parathyroids: effects of calcium, isoproterenol and growth factors. Mol Cell Endocrinol. 1983 Jun;30(3):313–328. doi: 10.1016/0303-7207(83)90067-9. [DOI] [PubMed] [Google Scholar]
  13. Motokura T., Bloom T., Kim H. G., Jüppner H., Ruderman J. V., Kronenberg H. M., Arnold A. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature. 1991 Apr 11;350(6318):512–515. doi: 10.1038/350512a0. [DOI] [PubMed] [Google Scholar]
  14. Naveh-Many T., Rahamimov R., Livni N., Silver J. Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D. J Clin Invest. 1995 Oct;96(4):1786–1793. doi: 10.1172/JCI118224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Portale A. A., Booth B. E., Halloran B. P., Morris R. C., Jr Effect of dietary phosphorus on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest. 1984 Jun;73(6):1580–1589. doi: 10.1172/JCI111365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Portale A. A., Halloran B. P., Morris R. C., Jr Physiologic regulation of the serum concentration of 1,25-dihydroxyvitamin D by phosphorus in normal men. J Clin Invest. 1989 May;83(5):1494–1499. doi: 10.1172/JCI114043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Quarles L. D., Yohay D. A., Carroll B. A., Spritzer C. E., Minda S. A., Bartholomay D., Lobaugh B. A. Prospective trial of pulse oral versus intravenous calcitriol treatment of hyperparathyroidism in ESRD. Kidney Int. 1994 Jun;45(6):1710–1721. doi: 10.1038/ki.1994.223. [DOI] [PubMed] [Google Scholar]
  18. Reinhardt T. A., Horst R. L., Orf J. W., Hollis B. W. A microassay for 1,25-dihydroxyvitamin D not requiring high performance liquid chromatography: application to clinical studies. J Clin Endocrinol Metab. 1984 Jan;58(1):91–98. doi: 10.1210/jcem-58-1-91. [DOI] [PubMed] [Google Scholar]
  19. Reiss E., Canterbury J. M., Bercovitz M. A., Kaplan E. L. The role of phosphate in the secretion of parathyroid hormone in man. J Clin Invest. 1970 Nov;49(11):2146–2149. doi: 10.1172/JCI106432. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rosenberg C. L., Kim H. G., Shows T. B., Kronenberg H. M., Arnold A. Rearrangement and overexpression of D11S287E, a candidate oncogene on chromosome 11q13 in benign parathyroid tumors. Oncogene. 1991 Mar;6(3):449–453. [PubMed] [Google Scholar]
  21. Rutherford W. E., Bordier P., Marie P., Hruska K., Harter H., Greenwalt A., Blondin J., Haddad J., Bricker N., Slatopolsky E. Phosphate control and 25-hydroxycholecalciferol administration in preventing experimental renal osteodystrophy in the dog. J Clin Invest. 1977 Aug;60(2):332–341. doi: 10.1172/JCI108781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Schaefer K., Erley C. M., von Herrath D., Stein G. Calcium salts of ketoacids as a new treatment strategy for uremic hyperphosphatemia. Kidney Int Suppl. 1989 Nov;27:S136–S139. [PubMed] [Google Scholar]
  23. Slatopolsky E., Bricker N. S. The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Int. 1973 Aug;4(2):141–145. doi: 10.1038/ki.1973.92. [DOI] [PubMed] [Google Scholar]
  24. Slatopolsky E., Caglar S., Gradowska L., Canterbury J., Reiss E., Bricker N. S. On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using "proportional reduction" of dietary phosphorus intake. Kidney Int. 1972 Sep;2(3):147–151. doi: 10.1038/ki.1972.84. [DOI] [PubMed] [Google Scholar]
  25. Slatopolsky E., Caglar S., Pennell J. P., Taggart D. D., Canterbury J. M., Reiss E., Bricker N. S. On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest. 1971 Mar;50(3):492–499. doi: 10.1172/JCI106517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Yi H., Fukagawa M., Yamato H., Kumagai M., Watanabe T., Kurokawa K. Prevention of enhanced parathyroid hormone secretion, synthesis and hyperplasia by mild dietary phosphorus restriction in early chronic renal failure in rats: possible direct role of phosphorus. Nephron. 1995;70(2):242–248. doi: 10.1159/000188591. [DOI] [PubMed] [Google Scholar]

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