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Parathyroid hormone secretion and action

INTRODUCTION

Parathyroid hormone (PTH) is one of the two major hormones modulating calcium and phosphate homeostasis, the other being calcitriol (1,25-dihydroxyvitamin D) [1]. The minute-to-minute regulation of serum ionized calcium is exclusively regulated through PTH, maintaining the concentration of this cation within a narrow range, through stimulation of renal tubular calcium reabsorption and bone resorption [2,3]. On a more chronic basis, PTH also stimulates the conversion of calcidiol (25-hydroxyvitamin D) to calcitriol in renal tubular cells, thereby stimulating intestinal calcium absorption. (See "Chapter 6F: Hormonal regulation of calcium and phosphate balance".)

PTH secretion is, in turn, regulated by serum ionized calcium acting via an exquisitely sensitive calcium-sensing receptor on the surface of parathyroid cells [4]. The receptor has a long amino terminus, seven transmembrane segments, and a shorter intracellular carboxyl terminus (graph 1). When activated by a small increase in serum ionized calcium, the calcium-receptor complex acts via one or more guanine nucleotide-binding (G) protein through second messengers such as intracellular calcium and inositol phosphates to inhibit PTH secretion. Conversely, the effect of deactivation of the receptor by a small decrease in serum ionized calcium is to stimulate PTH secretion.

NORMAL PTH SECRETION

PTH synthesis and degradation — PTH is synthesized as a 115- amino acid polypeptide called pre-pro-PTH, which is cleaved within parathyroid cells at the N-terminal portion first to pro-PTH (90 amino acids) and then to PTH (84 amino acids). The latter is the major storage, secreted, and biologically active form of the hormone [5,6]. The biosynthetic process is estimated to take less than one hour. The N-terminal cleaved portions are rich in hydrophobic amino acids that are necessary for transport into the endoplasmic reticulum and cleavage into the mature 1-84 molecule [6]. The C-terminal portion of PTH is also essential for the PTH secretory process [6]. PTH 1-84 is secreted by exocytosis within seconds after induction of hypocalcemia [5]. Calcium regulates not only the release but also the synthesis and degradation of PTH, in all its molecular forms as described below [7].

In addition to intact PTH, some inactive carboxyl-terminal fragments and small amounts of active amino-terminal fragments of PTH are present in the parathyroid glands. During hypocalcemia, intracellular degradation of PTH decreases, and mostly PTH 1-84 is secreted; in comparison, during hypercalcemia mostly biologically inactive carboxyl-terminal fragments of PTH are secreted [1,3,7]. Under normocalcemic conditions, PTH 1-84 constitutes 20 percent of total circulating PTH molecules. This proportion increases to 33 percent under hypocalcemic conditions, and decreases to 4 percent in the presence of hypercalcemia [7]. Once secreted, PTH is rapidly cleared from plasma through uptake principally by the liver and kidney, where PTH 1-84 is cleaved into amino- and carboxyl-terminal fragments that are then cleared by the kidney.

Intact PTH has a plasma half-life of two to four minutes. In comparison, the C-terminal fragments, which are cleared principally by the kidney, has a half-life that is five to ten times greater. As a result, circulating immunoreactive PTH in normal subjects comprises:
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References Top
  1. Potts, JT, Juppner, H. Parathyroid hormone: molecular biology and regulation. In: Bilezikian, JP, Raisz, LG, Rodan, GA (Eds), Principles of Bone Biology, Academic Press, New York 1996. p. 325.
  2. Brown, EM. Four parameter model of the sigmoidal relationship between PTH release and extracellular in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab 1983; 56:572.
  3. Diaz, R, El-Hajj Fuleihan, G, Brown, EM. Regulation of parathyroid function. In: Handbook of Physiology, Section 7: Endocrinology, Vol.III, Hormonal regulation of water and electrolyte balance. Fray, GGS, (Ed), Oxford University Press, New York 1999.
  4. Brown, EM, Pollak, M, Seidman, CE, et al. Calcium-ion-sensing cell-surface receptors. N Engl J Med 1995; 333:234.
  5. Habener, JF, Kemper, BW, Rich, A, Potts, JT Jr. Biosynthesis of parathyroid hormone. Recent Prog Horm Res 1976; 33:249.
  6. Murray, TM, Rao, LG, Divieti, P, Bringhurst, FR. Parathyroid hormone secretion and action: evidence for discrete receptors for the carboxyl-terminal region and related biological actions of carboxyl- terminal ligands. Endocr Rev 2005; 26:78.
  7. D'Amour, P, Rakel, A, Brossard, JH, et al. Acute regulation of circulating parathyroid hormone (PTH) molecular forms by calcium: utility of PTH fragments/PTH(1-84) ratios derived from three generations of PTH assays. J Clin Endocrinol Metab 2006; 91:283.
  8. Juppner, H, Abou-Samra, AB, Freeman, M, et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 1991; 254:1024.
  9. Dunlay R, Hruska K. PTH receptor coupling to phospholipase C is an alternate pathway of signal transduction in bone and kidney. Am J Physiol 1990; 258:F223.
  10. Hruska, KA, Moskowitz, D, Esbrit, P, et al. Stimulation of inositol trisphosphate and diacylglycerol production in renal tubular cells by parathyroid hormone. J Clin Invest 1987; 79:230.
  11. Abou-Samra, AB, Jueppner, H, Westerberg, D, et al. Parathyroid hormone causes translocation of protein kinase-C from cytosol to membranes in rat osteosarcoma cells. Endocrinology 1989; 124:1107.
  12. Murrills, RJ, Matteo, JJ, Samuel, RL, et al. In vitro and in vivo activities of C-terminally truncated PTH peptides reveal a disconnect between cAMP signaling and functional activity. Bone 2004; 35:1263.
  13. Juppner, H, Potts, JT Jr. Immunoassays for the detection of parathyroid hormone. J Bone Miner Res 2002; 17 Suppl 2:N81.
  14. Haden, ST, Brown, EM, Hurwitz, S, et al. The effects of age and gender on parathyroid hormone dynamics. Clin Endocrinol (Oxf) 2000; 52:329.
  15. Naveh-Many, T, Friedlaender, MM, Mayer, H, Silver, J. Calcium regulates parathyroid hormone messenger ribonucleic acid (mRNA), but not calcitonin mRNA in vivo in the rat. Dominant role of 1,25-dihydroxyvitamin D. Endocrinology 1989; 125:275.
  16. El-Hajj Fuleihan, G. Strontium ranelate: a novel therapy for osteoporosis or a permutation of the same? Editorial. N Engl J Med 2004; 350: 504.
  17. Adler, AJ, Ferran, N, Berlyne, GM. Effects of inorganic phosphate on serum ionized calcium concentration in vitro: a reassessment of the "trade-off hypothesis". Kidney Int 1985; 28:932.
  18. Naveh-Many, T, Rahaminov, R, Livini, N, et al. Parathyroid cell proliferation in normal and chronic renal failure in rats: the effects of calcium, phosphate and vitamin D. J Clin Invest 1995; 96:1786.
  19. Slatopolsky, E, Finch, J, Denda, M, et al. Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 1996; 97:2534.
  20. Fine, A, Cox, D, Fontaine, B. Elevation of serum phosphate levels affects parathyroid hormone levels in only 50% of hemodialysis patients, which is unrelated to changes in serum calcium. J Am Soc Nephrol 1993; 3:1947.
  21. Cole, DE, Peltekova, VD, Rubin, LA, et al. A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations. Lancet 1999; 353:112.
  22. Pollak, MR, Brown, EM, Chou, YH, et al. Mutations in the human Ca2+-sensing receptor gene causes familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993; 75:1297.
  23. Pollak, MR, Chou, YH, Marx, SJ, et al. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype. J Clin Invest 1994; 93:1108.
  24. Pollak, MR, Brown, EM, Estep, HL, et al. Autosomal dominant hypocalcaemia caused by a Ca2+-sensing receptor gene mutation. Nat Genet 1994; 8:303.
  25. El-Hajj Fuleihan, G, Brown, EM, Heath, H. The Familial Benign Hypocalciuric Hypercalcemic Syndromes. In: "Principles of Bone Biology" Eds Bilezikian JP, Raisz LG, Rodan GA. Academic Press 2002, San Diego, CA.
  26. Yano, S, Sugimoto, T, Tsukamoto, T, et al. Association of decreased calcium-sensing receptor expression with proliferation of parathyroid cells in secondary hyperparathyroidism. Kidney Int 2000; 58:1980.
  27. Canadillas, S, Canalejo, A, Santamaria, R, et al. Calcium-sensing receptor expression and parathyroid hormone secretion in hyperplastic parathyroid glands from humans. J Am Soc Nephrol 2005; 16:2190.
  28. Brown, EM. Lithium induces abnormal calcium-regulated PTH release in dispersed bovine parathyroid cells. J Clin Endocrinol Metab 1981; 52:1046.
  29. Haden, ST, Stoll, AL, McCormick, S, et al. Alterations in parathyroid hormone dynamics in lithium-treated subjects. J Clin Endocrinol Metab 1997; 82:2844.
  30. Kallner, G, Petterson, U. Renal, thyroid, and parathyroid function during lithium treatment: laboratory tests in 207 people treated for 1-30 years. Acta Psychiatr Scand 1995; 91:48.
  31. Silverberg, SJ, Bone, HG III, Mariott, TB, et al. Short-term inhibition of parathyroid hormone secretion by a calcium receptor agonist in primary hyperparathyroidism. N Engl J Med 1997; 337:1506.
  32. Goodman, WG, Frazao, JM, Goodkin, DA, et al. A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Kidney Int 2000; 58:436.
  33. Martin, KJ, Gonzalez, EA, Gellens, M, et al. 19-Nor-1-alpha-25-dihydroxyvitamin D2 (Paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol 1998; 9:1427.
  34. Tan, AU, Levine, BS, Mazess, RB, et al. Effective suppression of parathyroid hormone by 1-alpha-hydroxy-vitamin D2 in hemodialysis patients with moderate to severe secondary hyperparathyroidism. Kidney Int 1997; 51:317.
  35. Segre, GV. Receptors for parathyroid hormone and parathyroid-hormone related protein. In: Bilzekian, JP, Raisz, LG, Rodan, GA (Eds), Principles of Bone Biology, Academic Press, New York 1996. p. 377.
  36. Karperien, M, van der, Harten HJ, van Schooten, R, et al. A frame-shift mutation in the type I parathyroid hormone (PTH)/PTH-related peptide receptor causing Blomstrand lethal osteochondrodysplasia. J Clin Endocrinol Metab 1999; 84:3713.
  37. Wysolmerski, JJ, Cormier, S, Philbrick, WM, et al. Absence of functional type 1 parathyroid hormone (PTH)/PTH-related protein receptors in humans is associated with abnormal breast development and tooth impaction. J Clin Endocrinol Metab 2001; 86:1788.
  38. Talmage, RV, Elliott, JR. Removal of calcium from bone as influenced by the parathyroids. Endocrinology 1958; 62:717.
  39. Yasuda, H, Shima, N, Nakagawa, N, et al. Osteoblast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANK. Proc Natl Acad Sci U S A 1998; 95:3597.
  40. Lee, SK, Lorenzo, JA. Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation. Endocrinology 1999; 140:3552.
  41. Silverberg, SJ, Shane, E, de la Cruz, L, et al. Skeletal disease in primary hyperparathyroidism. J Bone Miner Res 1989; 4:283.
  42. Parisien M, Silberberg SJ, Shane, E, et al. The histomorphometry of bone in primary hyperparathyroidism: preservation of cancellous bone structure. J Clin Endocrinol Metab 1990; 70:930.
  43. Lindsay, R, Nieves,J, Formica,C, et al. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 1997; 350:550.
  44. Finkelstein, JS, Klibanski, A, Schaefer, EH, et al. Parathyroid hormone for the prevention of bone loss induced by estrogen. N Engl J Med 1994; 331:1618.
  45. Neer, RM, Arnaud, CD, Zanchetta, JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344:1434.
  46. Hodsman, AB, Bauer, DC, Dempster, DW, et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev 2005; 26:688.
  47. Mohan, S, Kutilek, S, Zhang, C, et al. Comparison of bone formation responses to parathyroid hormone(1-34), (1-31), and (2-34) in mice. Bone 2000; 27:471.
  48. Friedman, PA, Gesek, FA. Calcium transport in renal epithelial cells. Am J Physiol 1993; 264:F181.
  49. van Abel, M, Hoenderop, JG, van der, Kemp AW, et al. Coordinated control of renal Ca(2+) transport proteins by parathyroid hormone. Kidney Int 2005; 68:1708.
  50. Gesek, FA, Friedman, PA. On the mechanism of parathyroid hormone stimulation of calcium uptake by mouse distal convoluted tubule cells. J Clin Invest 1992; 90:749.
  51. Hebert, SC. Extracellular calcium-sensing receptor: Implications for calcium and magnesium handling in the kidney. Kidney Int 1996; 50:2129.
  52. el-Hajj Fuleihan, G, Seifter, J, Scott, J, Brown, EM. Calcium-regulated renal calcium handling in healthy men: relationship to sodium handling. J Clin Endocrinol Metab 1998; 83:2366.
  53. Murer, H, Lotscher, M, Kaissling, B, et al. Renal brush border membrane Na/Pi-cotransport: Molecular aspects in PTH-dependent and dietary regulation. Kidney Int 1996; 49:1769.
  54. Pfister, MF, Lederer, E, Forgo, J, et al. Parathyroid hormone-dependent degradation of type II Na+/Pi cotransporters. J Biol Chem 1997; 272:20125.
  55. Broadus, AE, Horst, RL, Lang, R, et al. The importance of circulating 1,25-dihydroxyvitamin D in the pathogenesis of hypercalciuria and renal-stone formation in primary hyperparathyroidism. N Engl J Med 1980; 302:421.
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