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Journal List > J Clin Invest > v.101(12); Jun 15, 1998

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J Clin Invest. 1998 June 15; 101(12): 2812–2820.
doi: 10.1172/JCI2940.
PMCID: PMC508872
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Regulation of murine fetal-placental calcium metabolism by the calcium-sensing receptor.
C S Kovacs, C L Ho-Pao, J L Hunzelman, B Lanske, J Fox, J G Seidman, C E Seidman, and H M Kronenberg
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
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Abstract
The calcium-sensing receptor (CaSR) regulates PTH secretion to control the extracellular calcium concentration in adults, but its role in fetal life is unknown. We used CaSR gene knockout mice to investigate the role of the CaSR in regulating fetal calcium metabolism. The normal calcium concentration in fetal blood is raised above the maternal level, an increase that depends upon PTH-related peptide (PTHrP). Heterozygous (+/-) and homozygous (-/-) disruption of the CaSR caused a further increase in the fetal calcium level. This increase was modestly blunted by concomitant disruption of the PTHrP gene and completely reversed by disruption of the PTH/ PTHrP receptor gene. Serum levels of PTH and 1, 25-dihydroxyvitamin D were substantially increased above the normal low fetal levels by disruption of the CaSR. The free deoxypyridinoline level was increased in the amniotic fluid (urine) of CaSR-/- fetuses; this result suggests that fetal bone resorption is increased. Placental calcium transfer was reduced, and renal calcium excretion was increased, by disruption of the CaSR. These studies indicate that the CaSR normally suppresses PTH secretion in the presence of the normal raised (and PTHrP-dependent) fetal calcium level. Disruption of the CaSR causes fetal hyperparathyroidism and hypercalcemia, with additional effects on placental calcium transfer.
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Selected References
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  • Brown EM, Pollak M, Seidman CE, Seidman JG, Chou YH, Riccardi D, Hebert SC. Calcium-ion-sensing cell-surface receptors. N Engl J Med. 1995 Jul 27;333(4):234–240. [PubMed]
  • Chattopadhyay N, Mithal A, Brown EM. The calcium-sensing receptor: a window into the physiology and pathophysiology of mineral ion metabolism. Endocr Rev. 1996 Aug;17(4):289–307. [PubMed]
  • Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature. 1993 Dec 9;366(6455):575–580. [PubMed]
  • Riccardi D, Park J, Lee WS, Gamba G, Brown EM, Hebert SC. Cloning and functional expression of a rat kidney extracellular calcium/polyvalent cation-sensing receptor. Proc Natl Acad Sci U S A. 1995 Jan 3;92(1):131–135. [PubMed]
  • Garrett JE, Tamir H, Kifor O, Simin RT, Rogers KV, Mithal A, Gagel RF, Brown EM. Calcitonin-secreting cells of the thyroid express an extracellular calcium receptor gene. Endocrinology. 1995 Nov;136(11):5202–5211. [PubMed]
  • Ruat M, Molliver ME, Snowman AM, Snyder SH. Calcium sensing receptor: molecular cloning in rat and localization to nerve terminals. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3161–3165. [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]
  • Pollak MR, Brown EM, Estep HL, McLaine PN, Kifor O, Park J, Hebert SC, Seidman CE, Seidman JG. Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation. Nat Genet. 1994 Nov;8(3):303–307. [PubMed]
  • Pearce SH, Williamson C, Kifor O, Bai M, Coulthard MG, Davies M, Lewis-Barned N, McCredie D, Powell H, Kendall-Taylor P, Brown EM, Thakker RV. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med. 1996 Oct 10;335(15):1115–1122. [PubMed]
  • Kovacs CS, Kronenberg HM. Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocr Rev. 1997 Dec;18(6):832–872. [PubMed]
  • Care AD, Caple IW, Abbas SK, Pickard DW. The effect of fetal thyroparathyroidectomy on the transport of calcium across the ovine placenta to the fetus. Placenta. 1986 Sep–Oct;7(5):417–424. [PubMed]
  • Weatherley AJ, Ross R, Pickard DW, Care AD. The transfer of calcium during perfusion of the placenta and intact and thyroparathyroidectomized sheep. Placenta. 1983 Jul–Sep;4(3):271–277. [PubMed]
  • Abbas SK, Pickard DW, Rodda CP, Heath JA, Hammonds RG, Wood WI, Caple IW, Martin TJ, Care AD. Stimulation of ovine placental calcium transport by purified natural and recombinant parathyroid hormone-related protein (PTHrP) preparations. Q J Exp Physiol. 1989 Jul;74(4):549–552. [PubMed]
  • Care AD, Abbas SK, Pickard DW, Barri M, Drinkhill M, Findlay JB, White IR, Caple IW. Stimulation of ovine placental transport of calcium and magnesium by mid-molecule fragments of human parathyroid hormone-related protein. Exp Physiol. 1990 Jul;75(4):605–608. [PubMed]
  • Kovacs CS, Lanske B, Hunzelman JL, Guo J, Karaplis AC, Kronenberg HM. Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15233–15238. [PubMed]
  • Dvir R, Golander A, Jaccard N, Yedwab G, Otremski I, Spirer Z, Weisman Y. Amniotic fluid and plasma levels of parathyroid hormone-related protein and hormonal modulation of its secretion by amniotic fluid cells. Eur J Endocrinol. 1995 Sep;133(3):277–282. [PubMed]
  • Thiébaud D, Janisch S, Koelbl H, Hanzal E, Jacquet AF, Leodolter S, Burckhardt P, Pecherstorfer M. Direct evidence of a parathyroid related protein gradient between the mother and the newborn in humans. Bone Miner. 1993 Dec;23(3):213–221. [PubMed]
  • Khosla S, Johansen KL, Ory SJ, O'Brien PC, Kao PC. Parathyroid hormone-related peptide in lactation and in umbilical cord blood. Mayo Clin Proc. 1990 Nov;65(11):1408–1414. [PubMed]
  • Chattopadhyay N, Baum M, Bai M, Riccardi D, Hebert SC, Harris HW, Brown EM. Ontogeny of the extracellular calcium-sensing receptor in rat kidney. Am J Physiol. 1996 Sep;271(3 Pt 2):F736–F743. [PubMed]
  • Ho C, Conner DA, Pollak MR, Ladd DJ, Kifor O, Warren HB, Brown EM, Seidman JG, Seidman CE. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet. 1995 Dec;11(4):389–394. [PubMed]
  • Karaplis AC, Luz A, Glowacki J, Bronson RT, Tybulewicz VL, Kronenberg HM, Mulligan RC. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev. 1994 Feb 1;8(3):277–289. [PubMed]
  • Lanske B, Karaplis AC, Lee K, Luz A, Vortkamp A, Pirro A, Karperien M, Defize LH, Ho C, Mulligan RC, Abou-Samra AB, Jüppner H, Segre GV, Kronenberg HM. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science. 1996 Aug 2;273(5275):663–666. [PubMed]
  • Wallach S, Verch RL. Placental transport of chromium. J Am Coll Nutr. 1984;3(1):69–74. [PubMed]
  • Symonds HW, Sansom BF, Twardock AR. The measurement of the transfer of calcium and phosphorus from foetus to dam in the sheep using a whole body counter. Res Vet Sci. 1972 May;13(3):272–275. [PubMed]
  • Ramberg CF, Jr, Delivoria-Papadopoulos M, Crandall ED, Kronfeld DS. Kinetic analysis of calcium transport across the placenta. J Appl Physiol. 1973 Nov;35(5):682–688. [PubMed]
  • Brommage R, DeLuca HF. Placental transport of calcium and phosphorus is not regulated by vitamin D. Am J Physiol. 1984 Apr;246(4 Pt 2):F526–F529. [PubMed]
  • Hellman P, Ridefelt P, Juhlin C, Akerström G, Rastad J, Gylfe E. Parathyroid-like regulation of parathyroid-hormone-related protein release and cytoplasmic calcium in cytotrophoblast cells of human placenta. Arch Biochem Biophys. 1992 Feb 14;293(1):174–180. [PubMed]
  • Tucci J, Russell A, Senior PV, Fernley R, Ferraro T, Beck F. The expression of parathyroid hormone and parathyroid hormone-related protein in developing rat parathyroid glands. J Mol Endocrinol. 1996 Oct;17(2):149–157. [PubMed]
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