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J Clin Invest. Oct 1995; 96(4): 1786–1793.
PMCID: PMC185815

Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D.

Abstract

Secondary hyperparathyroidism is characterized by an increase in parathyroid (PT) cell number, and parathyroid hormone (PTH) synthesis and secretion. It is still unknown as to what stimuli regulate PT cell proliferation and how they do this. We have studied rats with dietary-induced secondary hyper- and hypoparathyroidism, rats given 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and rats after 5/6 nephrectomy for the presence of PT cell proliferation and apoptosis. PT cell proliferation has been measured by staining for proliferating cell nuclear antigen (PCNA) and apoptosis by in situ detection of nuclear DNA fragmentation and correlated with serum biochemistry and PTH mRNA levels. A low calcium diet led to increased levels of PTH mRNA and a 10-fold increase in PT cell proliferation. A low phosphate diet led to decreased levels of PTH mRNA and the complete absence of PT cell proliferation. 1,25 (OH)2D3 (25 pmol/d x 3) led to a decrease in PTH mRNA levels and unlike the hypophosphatemic rats there was no decrease in cell proliferation. There were no cells undergoing apoptosis in any of the experimental conditions. The secondary hyperparathyroidism of 5/6 nephrectomized rats was characterized by an increase in PTH mRNA levels and PT cell proliferation which were both markedly decreased by a low phosphate diet. The number of PCNA positive cells was increased by a high phosphate diet. Therefore hypocalcemia, hyperphosphatemia and uremia lead to PT cell proliferation, and hypophosphatemia completely abolishes this effect. Injected 1,25 (OH)2D3 had no effect. These findings emphasize the importance of a normal phosphate and calcium in the prevention of PT cell hyperplasia.

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  • Naveh-Many T, Silver J. Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat. J Clin Invest. 1990 Oct;86(4):1313–1319. [PMC free article] [PubMed]
  • Kilav R, Silver J, Naveh-Many T. Parathyroid hormone gene expression in hypophosphatemic rats. J Clin Invest. 1995 Jul;96(1):327–333. [PMC free article] [PubMed]
  • Naveh-Many T, Almogi G, Livni N, Silver J. Estrogen receptors and biologic response in rat parathyroid tissue and C cells. J Clin Invest. 1992 Dec;90(6):2434–2438. [PMC free article] [PubMed]
  • Silver J, Naveh-Many T, Mayer H, Schmelzer HJ, Popovtzer MM. Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest. 1986 Nov;78(5):1296–1301. [PMC free article] [PubMed]
  • MacDonald PN, Ritter C, Brown AJ, Slatopolsky E. Retinoic acid suppresses parathyroid hormone (PTH) secretion and PreproPTH mRNA levels in bovine parathyroid cell culture. J Clin Invest. 1994 Feb;93(2):725–730. [PMC free article] [PubMed]
  • Svensson O, Wernerson A, Reinholt FP. Effect of calcium depletion on the rat parathyroids. Bone Miner. 1988 Jan;3(3):259–269. [PubMed]
  • Wernerson A, Widholm SM, Svensson O, Reinholt FP. Parathyroid cell number and size in hypocalcemic young rats. APMIS. 1991 Dec;99(12):1096–1102. [PubMed]
  • Castleman B, Mallory TB. Parathyroid Hyperplasia in Chronic Renal Insufficiency. Am J Pathol. 1937 Jul;13(4):553–574.7. [PMC free article] [PubMed]
  • Peters G. Cell cycle. Stifled by inhibitions. Nature. 1994 Sep 15;371(6494):204–205. [PubMed]
  • Miyachi K, Fritzler MJ, Tan EM. Autoantibody to a nuclear antigen in proliferating cells. J Immunol. 1978 Dec;121(6):2228–2234. [PubMed]
  • Almendral JM, Huebsch D, Blundell PA, Macdonald-Bravo H, Bravo R. Cloning and sequence of the human nuclear protein cyclin: homology with DNA-binding proteins. Proc Natl Acad Sci U S A. 1987 Mar;84(6):1575–1579. [PMC free article] [PubMed]
  • Krishna TS, Kong XP, Gary S, Burgers PM, Kuriyan J. Crystal structure of the eukaryotic DNA polymerase processivity factor PCNA. Cell. 1994 Dec 30;79(7):1233–1243. [PubMed]
  • Jaskulski D, deRiel JK, Mercer WE, Calabretta B, Baserga R. Inhibition of cellular proliferation by antisense oligodeoxynucleotides to PCNA cyclin. Science. 1988 Jun 10;240(4858):1544–1546. [PubMed]
  • Galand P, Degraef C. Cyclin/PCNA immunostaining as an alternative to tritiated thymidine pulse labelling for marking S phase cells in paraffin sections from animal and human tissues. Cell Tissue Kinet. 1989 Sep;22(5):383–392. [PubMed]
  • Raff MC. Social controls on cell survival and cell death. Nature. 1992 Apr 2;356(6368):397–400. [PubMed]
  • Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. [PMC free article] [PubMed]
  • Shvil Y, Naveh-Many T, Barach P, Silver J. Regulation of parathyroid cell gene expression in experimental uremia. J Am Soc Nephrol. 1990 Jul;1(1):99–104. [PubMed]
  • Okazaki T, Chung U, Nishishita T, Ebisu S, Usuda S, Mishiro S, Xanthoudakis S, Igarashi T, Ogata E. A redox factor protein, ref1, is involved in negative gene regulation by extracellular calcium. J Biol Chem. 1994 Nov 11;269(45):27855–27862. [PubMed]
  • Pe'er J, Gnessin H, Shargal Y, Livni N. PC-10 immunostaining of proliferating cell nuclear antigen in posterior uveal melanoma. Enucleation versus enucleation postirradiation groups. Ophthalmology. 1994 Jan;101(1):56–62. [PubMed]
  • Szabo A, Merke J, Beier E, Mall G, Ritz E. 1,25(OH)2 vitamin D3 inhibits parathyroid cell proliferation in experimental uremia. Kidney Int. 1989 Apr;35(4):1049–1056. [PubMed]
  • Demay MB, Kiernan MS, DeLuca HF, Kronenberg HM. Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8097–8101. [PMC free article] [PubMed]
  • Lu KP, Means AR. Regulation of the cell cycle by calcium and calmodulin. Endocr Rev. 1993 Feb;14(1):40–58. [PubMed]
  • Nemeth EF, Scarpa A. Rapid mobilization of cellular Ca2+ in bovine parathyroid cells evoked by extracellular divalent cations. Evidence for a cell surface calcium receptor. J Biol Chem. 1987 Apr 15;262(11):5188–5196. [PubMed]
  • Holmgren L, O'Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med. 1995 Feb;1(2):149–153. [PubMed]
  • ROTH SI, RAISZ LG. EFFECT OF CALCIUM CONCENTRATION ON THE ULTRASTRUCTURE OF RAT PARATHYROID IN ORGAN CULTURE. Lab Invest. 1964 Apr;13:331–345. [PubMed]
  • Brandi ML, Fitzpatrick LA, Coon HG, Aurbach GD. Bovine parathyroid cells: cultures maintained for more than 140 population doublings. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1709–1713. [PMC free article] [PubMed]
  • Kremer R, Bolivar I, Goltzman D, Hendy GN. Influence of calcium and 1,25-dihydroxycholecalciferol on proliferation and proto-oncogene expression in primary cultures of bovine parathyroid cells. Endocrinology. 1989 Aug;125(2):935–941. [PubMed]
  • Stanbury SW. Vitamin D and hyperparathyroidism: the Lumleian Lecture 1981. J R Coll Physicians Lond. 1981 Oct;15(4):205–217. [PubMed]
  • Rivkees SA, el-Hajj-Fuleihan G, Brown EM, Crawford JD. Tertiary hyperparathyroidism during high phosphate therapy of familial hypophosphatemic rickets. J Clin Endocrinol Metab. 1992 Dec;75(6):1514–1518. [PubMed]
  • Nygren P, Larsson R, Johansson H, Ljunghall S, Rastad J, Akerström G. 1,25(OH)2D3 inhibits hormone secretion and proliferation but not functional dedifferentiation of cultured bovine parathyroid cells. Calcif Tissue Int. 1988 Oct;43(4):213–218. [PubMed]
  • Reitsma PH, Rothberg PG, Astrin SM, Trial J, Bar-Shavit Z, Hall A, Teitelbaum SL, Kahn AJ. Regulation of myc gene expression in HL-60 leukaemia cells by a vitamin D metabolite. Nature. 1983 Dec 1;306(5942):492–494. [PubMed]
  • Lopez-Hilker S, Dusso AS, Rapp NS, Martin KJ, Slatopolsky E. Phosphorus restriction reverses hyperparathyroidism in uremia independent of changes in calcium and calcitriol. Am J Physiol. 1990 Sep;259(3 Pt 2):F432–F437. [PubMed]
  • Lucas PA, Brown RC, Woodhead JS, Coles GA. 1,25-dihydroxycholecalciferol and parathyroid hormone in advanced chronic renal failure: effects of simultaneous protein and phosphorus restriction. Clin Nephrol. 1986 Jan;25(1):7–10. [PubMed]
  • Lafage MH, Combe C, Fournier A, Aparicio M. Ketodiet, physiological calcium intake and native vitamin D improve renal osteodystrophy. Kidney Int. 1992 Nov;42(5):1217–1225. [PubMed]
  • Motokura T, Bloom T, Kim HG, Jüppner H, Ruderman JV, Kronenberg HM, Arnold A. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature. 1991 Apr 11;350(6318):512–515. [PubMed]
  • Motokura T, Arnold A. PRAD1/cyclin D1 proto-oncogene: genomic organization, 5' DNA sequence, and sequence of a tumor-specific rearrangement breakpoint. Genes Chromosomes Cancer. 1993 Jun;7(2):89–95. [PubMed]
  • Cryns VL, Thor A, Xu HJ, Hu SX, Wierman ME, Vickery AL, Jr, Benedict WF, Arnold A. Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma. N Engl J Med. 1994 Mar 17;330(11):757–761. [PubMed]
  • Law WM, Jr, Heath H., 3rd Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families. Ann Intern Med. 1985 Apr;102(4):511–519. [PubMed]
  • Khosla S, Ebeling PR, Firek AF, Burritt MM, Kao PC, Heath H., 3rd Calcium infusion suggests a "set-point" abnormality of parathyroid gland function in familial benign hypercalcemia and more complex disturbances in primary hyperparathyroidism. J Clin Endocrinol Metab. 1993 Mar;76(3):715–720. [PubMed]
  • Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell. 1993 Dec 31;75(7):1297–1303. [PubMed]
  • Friedman E, Sakaguchi K, Bale AE, Falchetti A, Streeten E, Zimering MB, Weinstein LS, McBride WO, Nakamura Y, Brandi ML, et al. Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1. N Engl J Med. 1989 Jul 27;321(4):213–218. [PubMed]
  • Thakker RV, Bouloux P, Wooding C, Chotai K, Broad PM, Spurr NK, Besser GM, O'Riordan JL. Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. N Engl J Med. 1989 Jul 27;321(4):218–224. [PubMed]
  • Ceccherini I, Romei C, Barone V, Pacini F, Martino E, Loviselli A, Pinchera A, Romeo G. Identification of the Cys634-->Tyr mutation of the RET proto-oncogene in a pedigree with multiple endocrine neoplasia type 2A and localized cutaneous lichen amyloidosis. J Endocrinol Invest. 1994 Mar;17(3):201–204. [PubMed]
  • Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Höppener JW, van Amstel HK, Romeo G, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994 Jan 27;367(6461):375–376. [PubMed]
  • Tsai MS, Ledger GA, Khosla S, Gharib H, Thibodeau SN. Identification of multiple endocrine neoplasia, type 2 gene carriers using linkage analysis and analysis of the RET proto-oncogene. J Clin Endocrinol Metab. 1994 May;78(5):1261–1264. [PubMed]
  • Arnold A, Brown MF, Ureña P, Gaz RD, Sarfati E, Drüeke TB. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest. 1995 May;95(5):2047–2053. [PMC free article] [PubMed]

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