Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1976 Sep;58(3):529–534. doi: 10.1172/JCI108497

Direct stimulation of bone resorption by thyroid hormones.

G R Mundy, J L Shapiro, J G Bandelin, E M Canalis, L G Raisz
PMCID: PMC333209  PMID: 182721

Abstract

Although hypercalcemia, osteoporosis, and increased bone turnover are associated with thyrotoxicosis, no direct effects of thyroid hormones on bone metabolism have been reported previously in organ culture. We have now demonstrated that prolonged treatment with thyroxine (T4) or triiodothyronine (T3) can directly increase bone resorption in cultured fetal rat long bones as measured by the release of previously incorporated 45Ca. T4 and T3 at 1 muM to 10 nM increased 45Ca release by 10-60% of total bone 45Ca during 5 days of culture. The medium contained 4 mg/ml of bovine serum albumin to which 90% of T4 and T3 were bound, so that free concentrations were less than 0.1 muM. The response to T4 and T3 was inhibited by cortisol (1 muM) and calcitonin (100 mU/ml). Indomethacin did not inhibit T4 response suggesting that T4 stimulation of bone resorption was not mediated by increased prostaglandin synthesis by the cultured bone. Matrix resorption was demonstrated by a decrease in extracted dry weight and hydroxyproline concentration of treated bones and by histologic examination which also showed increased osteoclast activity. The effects of thyroid hormones were not only slower than those of other potent stimulators of osteoclastic bone resorption (parathyroid hormone, vitamin D metabolites, osteoclast activating factor, and prostaglandins), but the maximum response was not as great. We conclude that T4 and T3 can directly stimulate bone resorption in vitro at concentrations approaching those which occur in thyrotoxicosis. This effect may explain the disturbances of calcium metabolism seen in hyperthyroidism.

Full text

PDF
529

Selected References

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

  1. Askenasi R., Demeester-Mirkine N. Urinary excretion of hydroxylysyl glycosides and thyroid function. J Clin Endocrinol Metab. 1975 Feb;40(2):342–344. doi: 10.1210/jcem-40-2-342. [DOI] [PubMed] [Google Scholar]
  2. BIGGERS J. D., GWATKIN R. B., HEYNER S. Growth of embryonic avian and mammalian tibiae on a relatively simple chemically defined medium. Exp Cell Res. 1961 Oct;25:41–58. doi: 10.1016/0014-4827(61)90305-6. [DOI] [PubMed] [Google Scholar]
  3. Castro J. H., Genuth S. M., Klein L. Comparative response to parathyroid hormone in hyperthyroidism and hypothyroidism. Metabolism. 1975 Jul;24(7):839–848. doi: 10.1016/0026-0495(75)90130-4. [DOI] [PubMed] [Google Scholar]
  4. Chase L. R., Aurbach G. D. The effect of parathyroid hormone on the concentration of adenosine 3',5'-monophosphate in skeletal tissue in vitro. J Biol Chem. 1970 Apr 10;245(7):1520–1526. [PubMed] [Google Scholar]
  5. Cheng P. T. An improved method for the determination of hydroxyproline in rat skin. J Invest Dermatol. 1969 Aug;53(2):112–115. doi: 10.1038/jid.1969.116. [DOI] [PubMed] [Google Scholar]
  6. Dietrich J. W., Canalis E. M., Maina D. M., Raisz L. G. Hormonal control of bone collagen synthesis in vitro: effects of parathyroid hormone and calcitonin. Endocrinology. 1976 Apr;98(4):943–949. doi: 10.1210/endo-98-4-943. [DOI] [PubMed] [Google Scholar]
  7. FOLLIS R. H., Jr Skeletal changes associated with hyperthyroidism. Bull Johns Hopkins Hosp. 1953 Jun;92(6):405–421. [PubMed] [Google Scholar]
  8. Feinblatt J. D., Raisz L. G. Secretion of thyrocalcitonin in organ culture. Endocrinology. 1971 Apr;88(4):797–804. doi: 10.1210/endo-88-4-797. [DOI] [PubMed] [Google Scholar]
  9. GAILLARD P. J. Observations on the effect of thyroid and parathyroid secretions on explanted mouse radius rudiments. Dev Biol. 1963 Mar;6:103–116. doi: 10.1016/0012-1606(63)90110-6. [DOI] [PubMed] [Google Scholar]
  10. HARRISON M. T., HARDEN R. M., ALEXANDER W. D. SOME EFFECTS OF PARATHYROID HORMONE IN THYROTOXICOSIS. J Clin Endocrinol Metab. 1964 Feb;24:214–217. doi: 10.1210/jcem-24-2-214. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Horton J. E., Raisz L. G., Simmons H. A., Oppenheim J. J., Mergenhagen S. E. Bone resorbing activity in supernatant fluid from cultured human peripheral blood leukocytes. Science. 1972 Sep 1;177(4051):793–795. doi: 10.1126/science.177.4051.793. [DOI] [PubMed] [Google Scholar]
  13. KRANE S. M., BROWNELL G. L., STANBURY J. B., CORRIGAN H. The effect of thyroid disease on calcium metabolism in man. J Clin Invest. 1956 Aug;35(8):874–887. doi: 10.1172/JCI103340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Karlberg B. E., Henriksson K. G., Andersson R. G. Cyclic adenosine 3',5'-monophosphate concentration in plasma, adipose tissue and skeletal muscle in normal subjects and in patients with hyper- and hypothyroidism. J Clin Endocrinol Metab. 1974 Jul;39(1):96–101. doi: 10.1210/jcem-39-1-96. [DOI] [PubMed] [Google Scholar]
  15. Klein D. C., Raisz L. G. Prostaglandins: stimulation of bone resorption in tissue culture. Endocrinology. 1970 Jun;86(6):1436–1440. doi: 10.1210/endo-86-6-1436. [DOI] [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. Lamki L., Row V. V., Volpé R. Cell-mediated immunity in Graves' disease and in Hashimoto's thyroiditis as shown by the demonstration of migration inhibition factor (MIF). J Clin Endocrinol Metab. 1973 Feb;36(2):358–364. doi: 10.1210/jcem-36-2-358. [DOI] [PubMed] [Google Scholar]
  18. Marcus R. Cyclic nucleotide phosphodiesterase from bone: characterization of the enzyme and studies of inhibition by thyroid hormones. Endocrinology. 1975 Feb;96(2):400–408. doi: 10.1210/endo-96-2-400. [DOI] [PubMed] [Google Scholar]
  19. Mundy G. R., Luben R. A., Raisz L. G., Oppenheim J. J., Buell D. N. Bone-resorbing activity in supernatants from lymphoid cell lines. N Engl J Med. 1974 Apr 18;290(16):867–871. doi: 10.1056/NEJM197404182901601. [DOI] [PubMed] [Google Scholar]
  20. Nejad I., Bollinger J., Mitnick M. A., Sullivan P., Reichlin S. Measurement of plasma and tissue triiodothyronine concentration in the rat by radioimmunoassay. Endocrinology. 1975 Mar;96(3):773–780. doi: 10.1210/endo-96-3-773. [DOI] [PubMed] [Google Scholar]
  21. RAISZ L. G. BONE RESORPTION IN TISSUE CULTURE. FACTORS INFLUENCING THE RESPONSE TO PARATHYROID HORMONE. J Clin Invest. 1965 Jan;44:103–116. doi: 10.1172/JCI105117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Raisz L. G., Luben R. A., Mundy G. R., Dietrich J. W., Horton J. E., Trummel C. L. Effect of osteoclast activating factor from human leukocytes on bone metabolism. J Clin Invest. 1975 Aug;56(2):408–413. doi: 10.1172/JCI108106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Raisz L. G., Niemann I. Effect of phosphate, calcium and magnesium on bone resorption and hormonal responses in tissue culture. Endocrinology. 1969 Sep;85(3):446–452. doi: 10.1210/endo-85-3-446. [DOI] [PubMed] [Google Scholar]
  24. Raisz L. G., Sandberg A. L., Goodson J. M., Simmons H. A., Mergenhagen S. E. Complement-dependent stimulation of prostaglandin synthesis and bone resorption. Science. 1974 Aug 30;185(4153):789–791. doi: 10.1126/science.185.4153.789. [DOI] [PubMed] [Google Scholar]
  25. Rude R. K., Oldham S. B., Singer F. R., Nicoloff J. T. Treatment of thyrotoxic hypercalcemia with propranolol. N Engl J Med. 1976 Feb 19;294(8):431–433. doi: 10.1056/NEJM197602192940807. [DOI] [PubMed] [Google Scholar]
  26. Smith D. A., Fraser S. A., Wilson G. M. Hyperthyroidism and calcium metabolism. Clin Endocrinol Metab. 1973 Jul;2(2):333–354. doi: 10.1016/s0300-595x(73)80047-7. [DOI] [PubMed] [Google Scholar]
  27. Trummel C. L., Mundy G. R., Raisz L. G. Release of osteoclast activating factor by normal human peripheral blood leukocytes. J Lab Clin Med. 1975 Jun;85(6):1001–1007. [PubMed] [Google Scholar]

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

RESOURCES