Abstract
Inhibitors of erythropoiesis have been found in the blood of uremic patients but their nature has not been identified. These patients have excess blood levels of parathyroid hormone (PTH) and it is possible that PTH inhibits erythropoiesis. The present study was undertaken to examine the effect of intact PTH molecules and some of its fragments on human peripheral blood and mouse bone marrow burst-forming units-erythroid (BFU-E), on mouse bone marrow erythroid colony-forming unit (CFU-E), and granulocyte macrophage progenitors (CFU-GM), and evaluate the interaction between PTH and erythropoietin (Ep) on human BFU-E. Intact PTH (1-84 bPTH) in concentrations (7.5-30 U/ml;) comparable to those found in blood of uremic patients produced marked and significant (P less than 0.01) inhibition of BFU-E and mouse marrow GFU-GM, but not of mouse marrow CFU-E. Inactivation of 1-84 bPTH abolished its action on erythropoiesis. Increasing the concentration of Ep in the media from 0.67 to 1.9 U/ml overcame the inhibitory effect of 1-84 bPTH on BFU-E. The N-terminal fragment of PTH (1-34 bPTH) and 53-84 hPTH had no effect on BFU-E. The results demonstrate that (a) either the intact PTH molecule or a C-terminal fragment(s) bigger than 53-84 moiety exerts the inhibitory effect on erythropoiesis, and (b) adequate amounts of Ep can overcome this action of PTH. The data provide one possible pathway for the participation of excess PTH in the genesis of the anemia of uremia.
Full text
PDFSelected References
These references are in PubMed. This may not be the complete list of references from this article.
- Arieff A. I., Massry S. G. Calcium metabolism of brain in acute renal failure. Effects of uremia, hemodialysis, and parathyroid hormone. J Clin Invest. 1974 Feb;53(2):387–392. doi: 10.1172/JCI107571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Arnaud C. D. Hyperparathyroidism and renal failure. Kidney Int. 1973 Aug;4(2):89–95. doi: 10.1038/ki.1973.87. [DOI] [PubMed] [Google Scholar]
- Aurbach G. D., Keutmann H. T., Niall H. D., Tregear G. W., O'Riordan J. L., Marcus R., Marx S. J., Potts J. T., Jr Structure, synthesis, and mechanism of action of parathyroid hormone. Recent Prog Horm Res. 1972;28:353–398. [PubMed] [Google Scholar]
- Berson S. A., Yalow R. S. Parathyroid hormone in plasma in adenomatous hyperparathyroidism, uremia, and bronchogenic carcinoma. Science. 1966 Nov 18;154(3751):907–909. doi: 10.1126/science.154.3751.907. [DOI] [PubMed] [Google Scholar]
- Borle A. B. Calcium metabolism at the cellular level. Fed Proc. 1973 Sep;32(9):1944–1950. [PubMed] [Google Scholar]
- Borle A. B. Calcium metabolism in HeLa cells and the effects of parathyroid hormone. J Cell Biol. 1968 Mar;36(3):567–582. doi: 10.1083/jcb.36.3.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Borle A. B. Kinetic analyses of calcium movements in cell cultures. 3. Effects of calcium and parathyroid hormone in kidney cells. J Gen Physiol. 1970 Feb;55(2):163–186. doi: 10.1085/jgp.55.2.163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Boxer M., Ellman L., Geller R., Wang C. A. Anemia in primary hyperparathyroidism. Arch Intern Med. 1977 May;137(5):588–593. [PubMed] [Google Scholar]
- Brown R. Plasma erythropoietin in chronic uraemia. Br Med J. 1965 Oct 30;2(5469):1036–1038. doi: 10.1136/bmj.2.5469.1036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- CALLEN I. R., LIMARZI L. R. Blood and bone marrow studies in renal disease. Am J Clin Pathol. 1950 Jan;20(1):3-23, illust. doi: 10.1093/ajcp/20.1.3. [DOI] [PubMed] [Google Scholar]
- Canterbury J. M., Levey G. S., Reiss E. Activation of renal cortical adenylate cyclase by circulating immunoreactive parathyroid hormone fragments. J Clin Invest. 1973 Feb;52(2):524–527. doi: 10.1172/JCI107211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Caro J., Brown S., Miller O., Murray T., Erslev A. J. Erythropoietin levels in uremic nephric and anephric patients. J Lab Clin Med. 1979 Mar;93(3):449–458. [PubMed] [Google Scholar]
- Chase L. R., Aurbach G. D. Renal adenyl cyclase: anatomically separate sites for parathyroid hormone and vasopressin. Science. 1968 Feb 2;159(3814):545–547. doi: 10.1126/science.159.3814.545. [DOI] [PubMed] [Google Scholar]
- Clinical conference: Hyperparathyroidism: recent studies. Ann Intern Med. 1973 Oct;79(4):566–581. [PubMed] [Google Scholar]
- Cogan M. G., Covey C. M., Arieff A. I., Wisniewski A., Clark O. H., Lazarowitz V., Leach W. Central nervous system manifestations of hyperparathyroidism. Am J Med. 1978 Dec;65(6):963–970. doi: 10.1016/0002-9343(78)90748-9. [DOI] [PubMed] [Google Scholar]
- DESFORGES J. F., DAWSON J. P. The anemia of renal failure. AMA Arch Intern Med. 1958 Feb;101(2):326–332. doi: 10.1001/archinte.1958.00260140158024. [DOI] [PubMed] [Google Scholar]
- Desforges J. F. Anemia in uremia. Arch Intern Med. 1970 Nov;126(5):808–811. [PubMed] [Google Scholar]
- Erslev A. J. Anemia of chronic renal disease. Arch Intern Med. 1970 Nov;126(5):774–780. [PubMed] [Google Scholar]
- Eschbach J. W., Adamson J. W., Cook J. D. Disorders of red blood cell production in uremia. Arch Intern Med. 1970 Nov;126(5):812–815. [PubMed] [Google Scholar]
- Freitag J., Martin K. J., Hruska K. A., Anderson C., Conrades M., Ladenson J., Klahr S., Slatopolsky E. Impaired parathyroid hormone metabolism in patients with chronic renal failure. N Engl J Med. 1978 Jan 5;298(1):29–32. doi: 10.1056/NEJM197801052980107. [DOI] [PubMed] [Google Scholar]
- GALLAGHER N. I., McCARTHY J. M., HART K. T., LANGE R. D. Evaluation of plasma erythropoietic-stimulating factors in anemic uremic patients. Blood. 1959 Jun;14(6):662–667. [PubMed] [Google Scholar]
- GURNEY C. W., JACOBSON L. O., GOLDWASSER E. The physiologic and clinical significance of erythropoietin. Ann Intern Med. 1958 Aug;49(2):363–370. doi: 10.7326/0003-4819-49-2-363. [DOI] [PubMed] [Google Scholar]
- Gallien-Lartigue O. Calcium and ionophore A-23187 as initiators of DNA replication in the pluripotent haemopoietic stem cell. Cell Tissue Kinet. 1976 Nov;9(6):533–540. doi: 10.1111/j.1365-2184.1976.tb01302.x. [DOI] [PubMed] [Google Scholar]
- Goldstein D. A., Chui L. A., Massry S. G. Effect of parathyroid hormone and uremia on peripheral nerve calcium and motor nerve conduction velocity. J Clin Invest. 1978 Jul;62(1):88–93. doi: 10.1172/JCI109118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goldstein D. A., Feinstein E. I., Chui L. A., Pattabhiraman R., Massry S. G. The relationship between the abnormalities in electroencephalogram and blood levels of parathyroid hormone in dialysis patients. J Clin Endocrinol Metab. 1980 Jul;51(1):130–134. doi: 10.1210/jcem-51-1-130. [DOI] [PubMed] [Google Scholar]
- Guisado R., Arieff A. I., Massry S. G., Lazarowitz V., Kerian A. Changes in the electroencephalogram in acute uremia. Effects of parathyroid hormone and brain electrolytes. J Clin Invest. 1975 Apr;55(4):738–745. doi: 10.1172/JCI107984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hruska K. A., Blondin J., Bass R., Santiago J., Thomas L., Altsheler P., Martin K., Klahr S. Effect of intact parathyroid hormone on hepatic glucose release in the dog. J Clin Invest. 1979 Oct;64(4):1016–1023. doi: 10.1172/JCI109538. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Iscove N. N., Sieber F., Winterhalter K. H. Erythroid colony formation in cultures of mouse and human bone marrow: analysis of the requirement for erythropoietin by gel filtration and affinity chromatography on agarose-concanavalin A. J Cell Physiol. 1974 Apr;83(2):309–320. doi: 10.1002/jcp.1040830218. [DOI] [PubMed] [Google Scholar]
- JOSKE R. A., MCALISTER J. M., PRANKERD T. A. Isotope investigations of red cell production and destruction in chronic renal disease. Clin Sci. 1956 Nov;15(4):511–522. [PubMed] [Google Scholar]
- KAYE M. The anemia associated with renal disease. J Lab Clin Med. 1958 Jul;52(1):83–100. [PubMed] [Google Scholar]
- Kaplan J. G. Membrane cation transport and the control of proliferation of mammalian cells. Annu Rev Physiol. 1978;40:19–41. doi: 10.1146/annurev.ph.40.030178.000315. [DOI] [PubMed] [Google Scholar]
- Katz A. I., Hampers C. L., Merrill J. P. Secondary hyperparathyroidism and renal osteodystrophy in chronic renal failure. Analysis of 195 patients, with observations on the effects of chronic dialysis, kidney transplantation and subtotal parathyroidectomy. Medicine (Baltimore) 1969 Sep;48(5):333–374. [PubMed] [Google Scholar]
- LOGE J. P., LANGE R. D., MOORE C. V. Characterization of the anemia associated with chronic renal insufficiency. Am J Med. 1958 Jan;24(1):4–18. doi: 10.1016/0002-9343(58)90357-7. [DOI] [PubMed] [Google Scholar]
- Levi J., Bessler H., Hirsch I., Djaldetti M. Increased RNA and heme synthesis in mouse erythroid precursors by parathyroid hormone. Acta Haematol. 1979;61(3):125–129. doi: 10.1159/000207644. [DOI] [PubMed] [Google Scholar]
- Mallette L. E., Bilezikian J. P., Heath D. A., Aurbach G. D. Primary hyperparathyroidism: clinical and biochemical features. Medicine (Baltimore) 1974 Mar;53(2):127–146. [PubMed] [Google Scholar]
- Massry S. G., Coburn J. W., Peacock M., Kleeman C. R. Turnover of endogenous parathyroid hormone in uremic patients and those undergoing hemodialysis. Trans Am Soc Artif Intern Organs. 1972;18(0):416–422. doi: 10.1097/00002480-197201000-00103. [DOI] [PubMed] [Google Scholar]
- Massry S. G., Goldstein D. A. Role of parathyroid hormone in uremic toxicity. Kidney Int Suppl. 1978 Jun;(8):S39–S42. [PubMed] [Google Scholar]
- Massry S. G., Goldstein D. A. The search for uremic toxin(s) "X" "X" = PTH. Clin Nephrol. 1979 Apr;11(4):181–189. [PubMed] [Google Scholar]
- Massry S. G. Is parathyroid hormone a uremic toxin? Nephron. 1977;19(3):125–130. doi: 10.1159/000180876. [DOI] [PubMed] [Google Scholar]
- Meytes D., Ma Ortega J. A., Shore N. A., Dukes P. P. Human erythroid burst-promoting activity produced by phytohemagglutinin-stimulated, radioresistant peripheral blood mononuclear cells. Blood. 1979 Nov;54(5):1050–1057. [PubMed] [Google Scholar]
- Misiti J., Spivak J. L. Erythropoiesis in vitro. Role of calcium. J Clin Invest. 1979 Dec;64(6):1573–1579. doi: 10.1172/JCI109618. [DOI] [PMC free article] [PubMed] [Google Scholar]
- NAETS J. P., HEUSE A. F. Measurement of erythropoietic stimulating factor in anemic patients with or without renal disease. J Lab Clin Med. 1962 Sep;60:365–374. [PubMed] [Google Scholar]
- Ogawa M., Grush O. C., O'Dell R. F., Hara H., MacEachern M. D. Circulating erythropoietic precursors assessed in culture: characterization in normal men and patients with hemoglobinopathies. Blood. 1977 Dec;50(6):1081–1092. [PubMed] [Google Scholar]
- Ohno Y., Rege A. B., Fisher J. W., Barona J. Inhibitors of erythroid colony-forming cells (CFU-E and BFU-E) in sera of azotemic patients with anemia of renal disease. J Lab Clin Med. 1978 Dec;92(6):916–923. [PubMed] [Google Scholar]
- Pappenheimer A. M., Wilens S. L. Enlargement of the Parathyroid Glands in Renal Disease. Am J Pathol. 1935 Jan;11(1):73–91. [PMC free article] [PubMed] [Google Scholar]
- Perris A. D., Whitfield J. F. Calcium homeostasis and erythropoietic control in the rat. Can J Physiol Pharmacol. 1971 Jan;49(1):22–35. doi: 10.1139/y71-004. [DOI] [PubMed] [Google Scholar]
- ROSCOE M. H. Anaemia and nitrogen retention in patients with chronic renal failure. Lancet. 1952 Mar 1;1(6705):444–445. doi: 10.1016/s0140-6736(52)91954-5. [DOI] [PubMed] [Google Scholar]
- Rasmussen H., Goodman D. B. Relationships between calcium and cyclic nucleotides in cell activation. Physiol Rev. 1977 Jul;57(3):421–509. doi: 10.1152/physrev.1977.57.3.421. [DOI] [PubMed] [Google Scholar]
- Roth S. I., Marshall R. B. Pathology and ultrastructure of the human parathyroid glands in chronic renal failure. Arch Intern Med. 1969 Oct;124(4):397–407. [PubMed] [Google Scholar]
- Shaw A. B. Haemolysis in chronic renal failure. Br Med J. 1967 Apr 22;2(5546):213–216. doi: 10.1136/bmj.2.5546.213. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stanley E. R., Metcalf D. Partial purification and some properties of the factor in normal and leukaemic human urine stimulating mouse bone marrow colony growth in vitro. Aust J Exp Biol Med Sci. 1969 Aug;47(4):467–483. doi: 10.1038/icb.1969.51. [DOI] [PubMed] [Google Scholar]
- Weinberg S. G., Lubin A., Wiener S. N., Deoras M. P., Ghose M. K., Kopelman R. C. Myelofibrosis and renal osteodystrophy. Am J Med. 1977 Nov;63(5):755–764. doi: 10.1016/0002-9343(77)90162-0. [DOI] [PubMed] [Google Scholar]