Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1988 Aug;85(15):5673–5677. doi: 10.1073/pnas.85.15.5673

Direct action of the parathyroid hormone-like human hypercalcemic factor on bone.

D D Thompson 1, J G Seedor 1, J E Fisher 1, M Rosenblatt 1, G A Rodan 1
PMCID: PMC281822  PMID: 3399507

Abstract

Peptides containing residues 1-34 of the human parathyroid hormone (PTH)-like hypercalcemic factor (hHCF), termed hHCF-(1-34)-NH2, produce effects similar to those of PTH in several biological systems in vitro and in vivo. However, there is conflicting evidence regarding the potency of hHCF on bone and, by implication, its role in calcium mobilization and the skeletal contribution to tumor-associated hypercalcemia. To resolve this conflict, the effects of infusing either hHCF-(1-34)-NH2 or a peptide containing residues 1-34 of bovine PTH [bPTH-(1-34)] into unrestrained thyroparathyroidectomized rats on a low calcium diet were compared. Direct effects on bone histology and serum calcium levels, which are totally dependent on calcium mobilization from bone in these animals, were examined. bPTH-(1-34) and hHCF-(1-34)-NH2 were equipotent in producing dose-dependent calcium mobilization from bone. At an infusion rate of 0.1 nmol/hr, both peptides produced hypercalcemia and extensive nephrocalcinosis. Histomorphometric analysis of tibiae from these animals after 48 hr of peptide infusion showed a dose-related increase in osteoclast number from 3-5 cells per mm2 at 0.01 nmol/hr to approximately equal to 32 cells per mm2 at 0.1 nmol/hr of hHCF or bovine PTH. These findings indicate that hHCF has a direct PTH-like effect on bone and, in this model system, the hHCF-(1-34)-NH2 is equipotent to bPTH-(1-34).

Full text

PDF
5673

Images in this article

5675Image
on p.5675
5675Image
on p.5675
5675Image
on p.5675
5675Image
on p.5675

Selected References

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

  1. AMES B. N., DUBIN D. T. The role of polyamines in the neutralization of bacteriophage deoxyribonucleic acid. J Biol Chem. 1960 Mar;235:769–775. [PubMed] [Google Scholar]
  2. Benson R. C., Jr, Riggs B. L., Pickard B. M., Arnaud C. D. Radioimmunoassay of parathyroid hormone in hypercalcemic patients with malignant disease. Am J Med. 1974 Jun;56(6):821–826. doi: 10.1016/0002-9343(74)90810-9. [DOI] [PubMed] [Google Scholar]
  3. Horiuchi N., Caulfield M. P., Fisher J. E., Goldman M. E., McKee R. L., Reagan J. E., Levy J. J., Nutt R. F., Rodan S. B., Schofield T. L. Similarity of synthetic peptide from human tumor to parathyroid hormone in vivo and in vitro. Science. 1987 Dec 11;238(4833):1566–1568. doi: 10.1126/science.3685994. [DOI] [PubMed] [Google Scholar]
  4. Jaeger P., Jones W., Kashgarian M., Baron R., Clemens T. L., Segre G. V., Hayslett J. P. Animal model of primary hyperparathyroidism. Am J Physiol. 1987 Jun;252(6 Pt 1):E790–E798. doi: 10.1152/ajpendo.1987.252.6.E790. [DOI] [PubMed] [Google Scholar]
  5. Kemp B. E., Moseley J. M., Rodda C. P., Ebeling P. R., Wettenhall R. E., Stapleton D., Diefenbach-Jagger H., Ure F., Michelangeli V. P., Simmons H. A. Parathyroid hormone-related protein of malignancy: active synthetic fragments. Science. 1987 Dec 11;238(4833):1568–1570. doi: 10.1126/science.3685995. [DOI] [PubMed] [Google Scholar]
  6. Lorenzo J. A., Quinton J., Sousa S., Raisz L. G. Effects of DNA and prostaglandin synthesis inhibitors on the stimulation of bone resorption by epidermal growth factor in fetal rat long-bone cultures. J Clin Invest. 1986 Jun;77(6):1897–1902. doi: 10.1172/JCI112517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Mosekilde L., Melsen F. A tetracycline-based histomorphometric evaluation of bone resorption and bone turnover in hyperthyroidism and hyperparathyroidism. Acta Med Scand. 1978;204(1-2):97–102. doi: 10.1111/j.0954-6820.1978.tb08406.x. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Nissenson R. A., Strewler G. J., Williams R. D., Leung S. C. Activation of the parathyroid hormone receptor-adenylate cyclase system in osteosarcoma cells by a human renal carcinoma factor. Cancer Res. 1985 Nov;45(11 Pt 1):5358–5363. [PubMed] [Google Scholar]
  10. Rodan S. B., Insogna K. L., Vignery A. M., Stewart A. F., Broadus A. E., D'Souza S. M., Bertolini D. R., Mundy G. R., Rodan G. A. Factors associated with humoral hypercalcemia of malignancy stimulate adenylate cyclase in osteoblastic cells. J Clin Invest. 1983 Oct;72(4):1511–1515. doi: 10.1172/JCI111108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. 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]
  14. Stewart A. F., Mangin M., Wu T., Goumas D., Insogna K. L., Burtis W. J., Broadus A. E. Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats. J Clin Invest. 1988 Feb;81(2):596–600. doi: 10.1172/JCI113358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. 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]
  17. 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]
  18. 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]
  19. 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]
  20. Thiede M. A., Strewler G. J., Nissenson R. A., Rosenblatt M., Rodan G. A. Human renal carcinoma expresses two messages encoding a parathyroid hormone-like peptide: evidence for the alternative splicing of a single-copy gene. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4605–4609. doi: 10.1073/pnas.85.13.4605. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES