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. 1979 Nov;64(5):1238–1244. doi: 10.1172/JCI109578

Evidence for Skeletal Resistance to Parathyroid Hormone in Magnesium Deficiency

STUDIES IN ISOLATED PERFUSED BONE

Jeffrey J Freitag 1,2, Kevin J Martin 1,2, Mary B Conrades 1,2, Ezequiel Bellorin-Font 1,2, Steven Teitelbaum 1,2, Saulo Klahr 1,2, Eduardo Slatopolsky 1,2
PMCID: PMC371269  PMID: 227929

Abstract

Hypocalcemia during magnesium (Mg) depletion has been well described, but the precise mechanism(s) responsible for its occurrence is not yet fully understood. The hypocalcemia has been ascribed to decreased parathyroid hormone (PTH) secretion as well as skeletal resistance to PTH. Whereas the former is well established, controversy exists as to whether or not Mg depletion results in skeletal resistance to PTH. These studies examine the skeletal response to PTH in normal dogs and dogs fed a Mg-free diet for 4-6 mo. Isolated tibia from normal (serum Mg 1.83±0.1 mg/100 ml) and experimental dogs (serum Mg 1.34±0.15 mg/100 ml) were perfused with Krebs-Henseleit buffer during a constant infusion of 3 ng/ml of synthetic bovine PTH 1-34 (syn b-PTH 1-34). The arteriovenous (A-V) difference for immunoreactive PTH (iPTH) across seven normal bones was 37.5±3%. In contrast, the A-V difference for iPTH was markedly depressed to 10.1±1% across seven bones from Mg-depleted dogs. These findings correlated well with a biological effect (cyclic AMP [cAMP] production) of syn b-PTH 1-34 on bone. In control bones, cAMP production rose from a basal level of 5.8±0.2 to 17.5±0.7 pmol/min after syn b-PTH 1-34 infusion. In experimental bones, basal cAMP production was significantly lower than in controls, 4.5±0.1 pmol/min, and increased to only 7.1±0.4 pmol/min after syn b-PTH 1-34 infusion. Even when PTH concentrations were increased to 20 ng/ml, cAMP production by experimental bones was lower than in control bones perfused with 3 ng/ml. Histological examination of bones from Mg-deficient dogs showed a picture compatible with skeletal inactivity. These studies demonstrate decreased uptake of iPTH and diminished cAMP production by bone, which indicates skeletal resistance to PTH in chronic Mg deficiency.

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Selected References

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

  1. Anast C. S., Winnacker J. L., Forte L. R., Burns T. W. Impaired release of parathyroid hormone in magnesium deficiency. J Clin Endocrinol Metab. 1976 Apr;42(4):707–717. doi: 10.1210/jcem-42-4-707. [DOI] [PubMed] [Google Scholar]
  2. Buckle R. M., Care A. D., Cooper C. W., Gitelman H. J. The influence of plasma magnesium concentration on parathyroid hormone secretion. J Endocrinol. 1968 Dec;42(4):529–534. doi: 10.1677/joe.0.0420529. [DOI] [PubMed] [Google Scholar]
  3. Catt K. J., Dufau M. L. Peptide hormone receptors. Annu Rev Physiol. 1977;39:529–557. doi: 10.1146/annurev.ph.39.030177.002525. [DOI] [PubMed] [Google Scholar]
  4. Chase L. R., Slatopolsky E. Secretion and metabolic efficacy of parthyroid hormone in patients with severe hypomagnesemia. J Clin Endocrinol Metab. 1974 Mar;38(3):363–371. doi: 10.1210/jcem-38-3-363. [DOI] [PubMed] [Google Scholar]
  5. Connor T. B., Toskes P., Mahaffey J., Martin L. G., Williams J. B., Walser M. Parathyroid function during chronic magnesium deficiency. Johns Hopkins Med J. 1972 Aug;131(2):100–117. [PubMed] [Google Scholar]
  6. Dunn M. J. Magnesium depletion in the rhesus monkey: induction of magnesium-dependent hypocalcaemia. Clin Sci. 1971 Oct;41(4):333–344. doi: 10.1042/cs0410333. [DOI] [PubMed] [Google Scholar]
  7. Estep H., Shaw W. A., Watlington C., Hobe R., Holland W., Tucker S. G. Hypocalcemia due to hypomagnesemia and reversible parathyroid hormone unresponsiveness. J Clin Endocrinol Metab. 1969 Jun;29(6):842–848. doi: 10.1210/jcem-29-6-842. [DOI] [PubMed] [Google Scholar]
  8. Frost H. M. Tetracycline-based histological analysis of bone remodeling. Calcif Tissue Res. 1969;3(3):211–237. doi: 10.1007/BF02058664. [DOI] [PubMed] [Google Scholar]
  9. Habener J. F., Potts J. T., Jr Relative effectiveness of magnesium and calcium on the secretion and biosynthesis of parathyroid hormone in vitro. Endocrinology. 1976 Jan;98(1):197–202. doi: 10.1210/endo-98-1-197. [DOI] [PubMed] [Google Scholar]
  10. Hahn T. J., Chase L. R., Avioli L. V. Effect of magnesium depletion on responsiveness to parathyroid hormone in parathyroidectomized rats. J Clin Invest. 1972 Apr;51(4):886–891. doi: 10.1172/JCI106883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hamilton J. W., Spierto F. W., MacGregor R. R., Cohn D. V. Studies on the biosynthesis in vitro of parathyroid hormone. II. The effect of calcium and magnesium on synthesis of parathyroid hormone isolated from bovine parathyroid tissue and incubation medium. J Biol Chem. 1971 May 25;246(10):3224–3233. [PubMed] [Google Scholar]
  12. Herrmann-Erlee M. P., Meer JM vd The effects of dibutyryl cyclic AMP, aminophylline and propranolol on PTE-induced bone resorption in vitro. Endocrinology. 1974 Feb;94(2):424–434. doi: 10.1210/endo-94-2-424. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Hurst R. O. A simplified approach to the use of determinants in the calculation of the rat equation for a complex enzyme system. Can J Biochem. 1967 Dec;45(12):2015–2039. doi: 10.1139/o67-235. [DOI] [PubMed] [Google Scholar]
  15. Kather H., Simon B. Adenylate cyclase of human fat cell ghosts. Stimulation of enzyme activity by parathyroid hormone. J Clin Invest. 1977 Apr;59(4):730–733. doi: 10.1172/JCI108692. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Klein D. C., Raisz L. G. Role of adenosine-3',5'-monophosphate in the hormonal regulation of bone resorption: studies with cultured fetal bone. Endocrinology. 1971 Sep;89(3):818–826. doi: 10.1210/endo-89-3-818. [DOI] [PubMed] [Google Scholar]
  17. Kraml M. A semi-automated determination of phospholipids. Clin Chim Acta. 1966 Apr;13(4):442–448. doi: 10.1016/0009-8981(66)90235-x. [DOI] [PubMed] [Google Scholar]
  18. Levi J., Massry S. G., Coburn J. W., Llach F., Kleeman C. R. Hypocalcemia in magnesium-depleted dogs: evidence for reduced responsiveness to parathyroid hormone and relative failure of parathyroid gland function. Metabolism. 1974 Apr;23(4):323–335. doi: 10.1016/0026-0495(74)90050-x. [DOI] [PubMed] [Google Scholar]
  19. MacManus J., Heaton F. W., Lucas P. W. A decreased response to parathyroid hormone in magnesium deficiency. J Endocrinol. 1971 Feb;49(2):253–258. doi: 10.1677/joe.0.0490253. [DOI] [PubMed] [Google Scholar]
  20. Macmanus J., Heaton F. W. The influence of magnesium on calcium release from bone in vitro. Biochim Biophys Acta. 1970 Aug 14;215(2):360–367. doi: 10.1016/0304-4165(70)90035-8. [DOI] [PubMed] [Google Scholar]
  21. Martin K. J., Freitag J. J., Conrades M. B., Hruska K. A., Klahr S., Slatopolsky E. Selective uptake of the synthetic amino terminal fragment of bovine parathyroid hormone by isolated perfused bone. J Clin Invest. 1978 Aug;62(2):256–261. doi: 10.1172/JCI109124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Martin K., Hruska K., Greenwalt A., Klahr S., Slatopolsky E. Selective uptake of intact parathyroid hormone by the liver: differences between hepatic and renal uptake. J Clin Invest. 1976 Oct;58(4):781–788. doi: 10.1172/JCI108529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mennes P., Rosenbaum R., Martin K., Slatopolsky E. Hypomagnesemia and impaired parathyroid hormone secretion in chronic renal disease. Ann Intern Med. 1978 Feb;88(2):206–209. doi: 10.7326/0003-4819-88-2-206. [DOI] [PubMed] [Google Scholar]
  24. Muldowney F. P., McKenna T. J., Kyle L. H., Freaney R., Swan M. Parathormone-like effect of magnesium replenishment in steatorrhea. N Engl J Med. 1970 Jan 8;282(2):61–68. doi: 10.1056/NEJM197001082820203. [DOI] [PubMed] [Google Scholar]
  25. Rasmussen H., Pechet M., Fast D. Effect of dibutyryl cyclic adenosine 3',5'-monophosphate, theophylline, and other nucleotides upon calcium and phosphate metabolism. J Clin Invest. 1968 Aug;47(8):1843–1850. doi: 10.1172/JCI105874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Reddy C. R., Coburn J. W., Hartenbower D. L., Friedler R. M., Brickman A. S., Massry S. G., Jowsey J. Studies on mechanisms of hypocalcemia of magnesium depletion. J Clin Invest. 1973 Dec;52(12):3000–3010. doi: 10.1172/JCI107498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rodriguez H. J., Morrison A., Slatopolsky E., Klahr S. Adenylate cyclase of human parathyroid gland. J Clin Endocrinol Metab. 1978 Aug;47(2):319–325. doi: 10.1210/jcem-47-2-319. [DOI] [PubMed] [Google Scholar]
  28. Rude R. K., Oldham S. B., Sharp C. F., Jr, Singer F. R. Parathyroid hormone secretion in magnesium deficiency. J Clin Endocrinol Metab. 1978 Oct;47(4):800–806. doi: 10.1210/jcem-47-4-800. [DOI] [PubMed] [Google Scholar]
  29. Sherwood L. M., Herrman I., Bassett C. A. Parathyroid hormone secretion in vitro: regulation by calcium and magnesium ions. Nature. 1970 Mar 14;225(5237):1056–1058. doi: 10.1038/2251056a0. [DOI] [PubMed] [Google Scholar]
  30. Steiner A. L., Kipnis D. M., Utiger R., Parker C. Radioimmunoassay for the measurement of adenosine 3',5'-cyclic phosphate. Proc Natl Acad Sci U S A. 1969 Sep;64(1):367–373. doi: 10.1073/pnas.64.1.367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Suh S. M., Csima A., Fraser D. Pathogenesis of hypocalcemia in magnesium depletion. Normal end-organ responsiveness to parathyroid hormone. J Clin Invest. 1971 Dec;50(12):2668–2678. doi: 10.1172/JCI106768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Suh S. M., Tashjian A. H., Jr, Matsuo N., Parkinson D. K., Fraser D. Pathogenesis of hypocalcemia in primary hypomagnesemia: normal end-organ responsiveness to parathyroid hormone, impaired parathyroid gland function. J Clin Invest. 1973 Jan;52(1):153–160. doi: 10.1172/JCI107159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Vaes G. Parathyroid hormone-like action of N6-2'-O-dibutyryladenosine-3'5' (cyclic)-monophosphate on bone explants in tissue culture. Nature. 1968 Aug 31;219(5157):939–940. doi: 10.1038/219939a0. [DOI] [PubMed] [Google Scholar]
  34. Wells H., Lloyd W. Effects of theophylline on the serum calcium of rats after parathyroidectomy and administration of parathyroid hormone. Endocrinology. 1967 Jul;81(1):139–144. doi: 10.1210/endo-81-1-139. [DOI] [PubMed] [Google Scholar]
  35. Williams L. T., Mullikin D., Lefkowitz R. J. Magnesium dependence of agonist binding to adenylate cyclase-coupled hormone receptors. J Biol Chem. 1978 May 10;253(9):2984–2989. [PubMed] [Google Scholar]

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