Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1988 Mar;81(3):932–938. doi: 10.1172/JCI113406

Effects of a synthetic peptide of a parathyroid hormone-related protein on calcium homeostasis, renal tubular calcium reabsorption, and bone metabolism in vivo and in vitro in rodents.

A J Yates 1, G E Gutierrez 1, P Smolens 1, P S Travis 1, M S Katz 1, T B Aufdemorte 1, B F Boyce 1, T K Hymer 1, J W Poser 1, G R Mundy 1
PMCID: PMC442548  PMID: 3343349

Abstract

A synthetic peptide corresponding to the first 34 amino acids of the parathyroid hormone-related protein (PTH-rP) produced by a human tumor associated with hypercalcemia was examined for skeletal and renal effects on calcium metabolism in vivo and in vitro. These effects were compared with those of human parathyroid hormone (1-34), hPTH (1-34). Equal doses of PTH-rP(1-34) and hPTH(1-34) produced equivalent stimulation of adenylate cyclase in vitro in bone cells and kidney cells and tubules. Subcutaneous injection of PTH-rP(1-34) in mice caused a significant dose-related increase in blood ionized calcium similar to that seen with hPTH(1-34) at equivalent doses. Repeated injections of equal doses of both peptides caused sustained hypercalcemia which was significantly greater in PTH-rP(1-34)-treated mice, although each induced comparable increases in histomorphometric indices of osteoclastic bone resorption. PTH-rP(1-34) and hPTH(1-34) also caused similar increases in bone resorption when incubated with fetal rat long bones in organ culture. Infusion of either peptide into thyroparathyroidectomized rats suppressed urinary calcium excretion and increased urinary excretion of cyclic AMP. PTH-rP appears to have similar effects to those of PTH on the skeleton, the kidney, and overall calcium homeostasis.

Full text

PDF
932

Images in this article

936Image
on p.936
936Image
on p.936
937Image
on p.937

Selected References

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

  1. Brooker G., Harper J. F., Terasaki W. L., Moylan R. D. Radioimmunoassay of cyclic AMP and cyclic GMP. Adv Cyclic Nucleotide Res. 1979;10:1–33. [PubMed] [Google Scholar]
  2. Brooker G., Terasaki W. L., Price M. G. Gammaflow: a completely automated radioimmunoassay system. Science. 1976 Oct 15;194(4262):270–276. doi: 10.1126/science.184530. [DOI] [PubMed] [Google Scholar]
  3. Burtis W. J., Wu T., Bunch C., Wysolmerski J. J., Insogna K. L., Weir E. C., Broadus A. E., Stewart A. F. Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. J Biol Chem. 1987 May 25;262(15):7151–7156. [PubMed] [Google Scholar]
  4. Chabardès D., Imbert M., Clique A., Montégut M., Morel F. PTH sensitive adenyl cyclase activity in different segments of the rabbit nephron. Pflugers Arch. 1975;354(3):229–239. doi: 10.1007/BF00584646. [DOI] [PubMed] [Google Scholar]
  5. Gutierrez G. E., Mundy G. R., Katz M. S. Adenylate cyclase of osteoblast-like cells from rat osteosarcoma is stimulated by calcitonin as well as parathyroid hormone. Endocrinology. 1984 Dec;115(6):2342–2346. doi: 10.1210/endo-115-6-2342. [DOI] [PubMed] [Google Scholar]
  6. Gutierrez G. E., Mundy G. R., Katz M. S. Alterations in hormone-sensitive adenylate cyclase of cloned rat osteosarcoma cells during long-term culture. J Bone Miner Res. 1986 Aug;1(4):319–326. doi: 10.1002/jbmr.5650010404. [DOI] [PubMed] [Google Scholar]
  7. Harinck H. I., Bijvoet O. L., Plantingh A. S., Body J. J., Elte J. W., Sleeboom H. P., Wildiers J., Neijt J. P. Role of bone and kidney in tumor-induced hypercalcemia and its treatment with bisphosphonate and sodium chloride. Am J Med. 1987 Jun;82(6):1133–1142. doi: 10.1016/0002-9343(87)90215-4. [DOI] [PubMed] [Google Scholar]
  8. Hock J. M., Simmons H. A., Schiess M. C., Raisz L. G. Use of osmotic minipumps for delivery of parathyroid hormone. Calcif Tissue Int. 1982 May;34(3):270–272. doi: 10.1007/BF02411249. [DOI] [PubMed] [Google Scholar]
  9. Hodges R. S., Merrifield R. B. Monitoring of solid phase peptide synthesis by an automated spectrophotometric picrate method. Anal Biochem. 1975 May 12;65(1-2):241–272. doi: 10.1016/0003-2697(75)90509-6. [DOI] [PubMed] [Google Scholar]
  10. McDonnell G. D., Dunstan C. R., Evans R. A., Carter J. N., Hills E., Wong S. Y., McNeil D. R. Quantitative bone histology in the hypercalcemia of malignant disease. J Clin Endocrinol Metab. 1982 Dec;55(6):1066–1072. doi: 10.1210/jcem-55-6-1066. [DOI] [PubMed] [Google Scholar]
  11. Moseley J. M., Kubota M., Diefenbach-Jagger H., Wettenhall R. E., Kemp B. E., Suva L. J., Rodda C. P., Ebeling P. R., Hudson P. J., Zajac J. D. Parathyroid hormone-related protein purified from a human lung cancer cell line. Proc Natl Acad Sci U S A. 1987 Jul;84(14):5048–5052. doi: 10.1073/pnas.84.14.5048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Mundy G. R., Ibbotson K. J., D'Souza S. M. Tumor products and the hypercalcemia of malignancy. J Clin Invest. 1985 Aug;76(2):391–394. doi: 10.1172/JCI111984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Percival R. C., Yates A. J., Gray R. E., Galloway J., Rogers K., Neal F. E., Kanis J. A. Mechanism of malignant hypercalcaemia in carcinoma of the breast. Br Med J (Clin Res Ed) 1985 Sep 21;291(6498):776–779. doi: 10.1136/bmj.291.6498.776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Powell D., Singer F. R., Murray T. M., Minkin C., Potts J. T., Jr Nonparathyroid humoral hypercalcemia in patients with neoplastic diseases. N Engl J Med. 1973 Jul 26;289(4):176–181. doi: 10.1056/NEJM197307262890403. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Rabbani S. A., Mitchell J., Roy D. R., Kremer R., Bennett H. P., Goltzman D. Purification of peptides with parathyroid hormone-like bioactivity from human and rat malignancies associated with hypercalcemia. Endocrinology. 1986 Mar;118(3):1200–1210. doi: 10.1210/endo-118-3-1200. [DOI] [PubMed] [Google Scholar]
  17. Ralston S. H., Fogelman I., Gardner M. D., Dryburgh F. J., Cowan R. A., Boyle I. T. Hypercalcaemia of malignancy: evidence for a nonparathyroid humoral agent with an effect on renal tubular handling of calcium. Clin Sci (Lond) 1984 Feb;66(2):187–191. doi: 10.1042/cs0660187. [DOI] [PubMed] [Google Scholar]
  18. Rude R. K., Sharp C. F., Jr, Fredericks R. S., Oldham S. B., Elbaum N., Link J., Irwin L., Singer F. R. Urinary and nephrogenous adenosine 3',5'-monophosphate in the hypercalcemia of malignancy. J Clin Endocrinol Metab. 1981 Apr;52(4):765–771. doi: 10.1210/jcem-52-4-765. [DOI] [PubMed] [Google Scholar]
  19. Simpson E. L., Mundy G. R., D'Souza S. M., Ibbotson K. J., Bockman R., Jacobs J. W. Absence of parathyroid hormone messenger RNA in nonparathyroid tumors associated with hypercalcemia. N Engl J Med. 1983 Aug 11;309(6):325–330. doi: 10.1056/NEJM198308113090601. [DOI] [PubMed] [Google Scholar]
  20. Stewart A. F., Horst R., Deftos L. J., Cadman E. C., Lang R., Broadus A. E. Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and nonhumoral groups. N Engl J Med. 1980 Dec 11;303(24):1377–1383. doi: 10.1056/NEJM198012113032401. [DOI] [PubMed] [Google Scholar]
  21. Stewart A. F., Insogna K. L., Goltzman D., Broadus A. E. Identification of adenylate cyclase-stimulating activity and cytochemical glucose-6-phosphate dehydrogenase-stimulating activity in extracts of tumors from patients with humoral hypercalcemia of malignancy. Proc Natl Acad Sci U S A. 1983 Mar;80(5):1454–1458. doi: 10.1073/pnas.80.5.1454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Stewart A. F., Vignery A., Silverglate A., Ravin N. D., LiVolsi V., Broadus A. E., Baron R. Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: uncoupling of bone cell activity. J Clin Endocrinol Metab. 1982 Aug;55(2):219–227. doi: 10.1210/jcem-55-2-219. [DOI] [PubMed] [Google Scholar]
  23. Stewart A. F., Wu T., Goumas D., Burtis W. J., Broadus A. E. N-terminal amino acid sequence of two novel tumor-derived adenylate cyclase-stimulating proteins: identification of parathyroid hormone-like and parathyroid hormone-unlike domains. Biochem Biophys Res Commun. 1987 Jul 31;146(2):672–678. doi: 10.1016/0006-291x(87)90581-x. [DOI] [PubMed] [Google Scholar]
  24. Strewler G. J., Stern P. H., Jacobs J. W., Eveloff J., Klein R. F., Leung S. C., Rosenblatt M., Nissenson R. A. Parathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone. J Clin Invest. 1987 Dec;80(6):1803–1807. doi: 10.1172/JCI113275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Strewler G. J., Williams R. D., Nissenson R. A. Human renal carcinoma cells produce hypercalcemia in the nude mouse and a novel protein recognized by parathyroid hormone receptors. J Clin Invest. 1983 Mar;71(3):769–774. doi: 10.1172/JCI110825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Suva L. J., Winslow G. A., Wettenhall R. E., Hammonds R. G., Moseley J. M., Diefenbach-Jagger H., Rodda C. P., Kemp B. E., Rodriguez H., Chen E. Y. A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science. 1987 Aug 21;237(4817):893–896. doi: 10.1126/science.3616618. [DOI] [PubMed] [Google Scholar]

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

RESOURCES