Abstract
There is marked homology between the parathyroid hormone (PTH) and PTH-related protein (PTHrP) molecules at the amino terminal but the rest of the molecules are quite different, providing immunologically distinct peptides. However, they interact with the same receptor. Thus, PTHrP mediates biological actions reminiscent of PTH. PTHrP gene is a single copy gene, producting one to three mRNA transcripts through alternative splicing of the carboxy terminal, encoding peptides of 139, 141 or 173 amino acids. Having been recently isolated from malignant tumours, PTHrP is now considered to be the major mediator of humoral hypercalcaemia of malignancy (HHM). The PTH-like effects of PTHrP on the kidney and bone have been well characterized. The increase in renal tubular calcium reabsorption and the reduction in tubular phosphate reabsorption with a concomitant rise in nephrogenous cyclic AMP constitute the pathophysiological changes in the renal handling of calcium and phosphate in HHM. The osteotropic contribution to the malignant hypercalcaemia has been validated by enhanced osteoclastic bone resorption — an indirect effect of the amino terminal portion of the PTHrP molecule on osteoblasts. However, PTHrP has also been detected in a large number of normal adult tissues/organs as well as in human and animal fetuses. Fetal plasma calcium is higher than maternal and this is achieved by active transport of calcium across the placenta. Using ovine placental perfusion models, PTHrP, which is believed to originate from fetal parathyroid glands and the placenta itself, has been demonstrated to sustain this calcium gradient. Active placental transport of magnesium, but not phosphate, was also shown to be enhanced by PTHrP. In lactating rat mammary gland, PTHrP mRNA is expressed in response to the sucking stimulus, an effect probably mediated by a rise in the plasma level of prolactin. PTHrP, in various molecular sizes, is present in high concentrations in milk. Potential roles of mammary-derived PTHrP include active calcium translocation from blood to milk and/or the facilitation of intestinal calcium absorption in the newborn animal. There is recent evidence for an opposing osteotropic action mediated by the carboxy terminal of PTHrP which directly inhibits osteoclastic function. This would act synergistically with the relative fetal hypercalcaemia to ensure adequate bone mineralization in the developing fetus. This postulate, as with the other potential physiological role(s) of PTHrP in fetal and neonatal calcium and phosphate metabolism, now awaits further research.
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References
Moseley JM, Kubota M, Diefenbach-Jagger H, Wettenhall REH, Kemp BE, Suva LJ, Rodda CP, Ebeling PR, Hudson PJ, Zajac JD, Martin TJ (1987) Parathyroid hormone-related protein purified from a human lung cancer cell line. Proc Natl Acad Sci USA 84: 5048–5052
Martin TJ, Allan EH, Caple IW, Danks JA, Diefenbach-Jagger H, Ebeling PR, Gillespie MT, Hammonds G, Heath JA, Hudson PJ, Kemp BE, Kubota M, Kukreja SC, Moesley JM, Ng KW, Raisz LG, Rodda CP, Simmons HA, Suva J, Wettenhall REH, Wood WI (1989) Parathyroid hormone-related protein: isolation, molecular cloning and mechanisms of actions. Recent Prog Horn Res 45: 467–506
Mangin M, Webb AC, Dreyer BE, Posillico JT, Ikeda K, Weir EC, Stewart AF, Bander NH, Milstone L, Barton DE, Francke U, Broadus AE (1988) Identification of a cDNA encoding a parathyroid hormone-like peptide form a human tumor associated with humoral hypercalcaemia of malignancy. Proc Natl Acad Sci USA 85: 597–601
Mangin M, Ikeda K, Dreyer BE, Milstone L, Broadus AE (1988) Two distinct tumor-derived, parathyroid hormone-like peptides result from alternative ribonucleic acid splicing. Mol Endocrinol 2: 1049–1055
Hammonds RG, McKay P, Winslow GA, Diefenbach-Jagger H, Grill V, Glatz J, Rodda CP, Moseley JM, Wood WI, Martin TJ (1989) Purification and characterization of recombinant human parathyroid hormone-related protein. J Biol Chem 264: 14806–14811
Danks JA, Ebeling PR, Hayman J, Chou ST, Moseley JM, Dunlop J, Kemp BE, Martin TJ (1989) Parathyroid hormone-related protein: immunohistochemical localization in cancers and in normal skin. J Bone Miner Res 4: 273–278
Moniz C, Dixit M, Burton P, Knight D, Nicolaides K, Tzannatos C, Malik A, Banga JP, McGregor AM (1990) Parathyroid hormone-related peptide in human fetal renal calcium homeostasis. J Endocrinol [Suppl] 124: 95
Moniz C, Burton PB, Malick AN, Dixit M, Banga JP, Nicolaides K, Quirke P, Knight DE, McGregor AM (1990) Parathyroid hormone-related peptide in normal human fetal development. J Mol Endocrinol 5: 259–266
Moseley JM, Hayman JA, Danks JA, Alcorn D, Grill V, Southby J, Horton MA (1991) Immunohistochemical detection of parathyroid hormone-related protein in human fetal epithelia. J Clin Endocrinol Metab 73: 478–484
MacIsaac RJ, Caple IW, Danks JA, Diefenbach-Jagger H, Grill V, Moseley JM, Southby J, Martin TJ (1991) Ontogeny of parathyroid hormone-related protein in the ovine parathyroid gland. Endocrinology 129: 757–764
Thiede MA, Rodan GA (1988) Expression of a calcium-mobilizing parathyroid hormone-like peptide in lactating mammary tissue. Science 242: 278–280
Rodda CP, Kobota M, Heath JA, Ebeling PR, Moseley JM, Care AD, Caple IW, Martin TJ (1988) Evidence for a novel parathyroid hormone-related protein in foetal lamb parathyroid glands and sheep placenta: comparisons with a similar protein implicated in humoral hypercalcaemia of malignancy. J Endocrinol 117: 261–271
Aaron JE, Abbas SK, Colwell A, Eastell R, Oakley BA, Russell RGG, Care AD (1992) Parathyroid gland hormones in the skeletal development of the ovine foetus: the effect of parathyroidectomy with calcium and phosphate infusion. Bone Miner 16: 121–129
Budayr AA, Halloran BP, King JC, Diep D, Nissenson RA, Strewler GJ (1989) High levels of a parathyroid hormone-like protein in milk. Proc Natl Acad Sci USA 86: 7183–7185
Jüppner H, Abou-Samra A-B, Freeman M, Kong XF, Schipani E, Richards J, Kolakowski LF Jr, Hock J, Potts JT Jr, Kronenberg HM, Segre GV (1991) A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 254: 1024–1026
Abou-Samra A-B, Jüppner H, Force T, Freeman M, Kong X-F, Schipani E, Urena P, Richards J, Bonventre JV, Potts JT Jr, Kronenberg HM, Segre GV (1992) Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol triphosphates and increases intracellular free calcium. Proc Natl Acad Sci USA 89: 2732–2736
Rizzoli R, Caverzasio J, Fleisch H, Bonjour J-P (1986) Parathyroid hormone-like changes in renal calcium and phosphate reabsorption induced by Leydig cell tumor in thyroparathyroidectomized rats. Endocrinology 119: 1004–1009
Pizurki L, Rizzoli R, Caverzasio J, Mundy G Bonjour J-P (1980) Factor derived form human lung carcinoma associated with hypercalcemia mimics the effects of parathyroid hormone on phosphate transport in cultured renal epithelia. J Bone Miner Res 3: 233–239
Sartori L, Insogna KL, Barrett PQ (1988) Renal phosphate transport in humoral hypercalcemia of malignancy. Am J Physiol, 255: F1078-F1084
Pizurki L, Rizzoli R, Moseley JM, Martin TJ, Caverzasio J, Bonjour J-P (1988) Effect of synthetic tumoral PTH-related peptide on cAMP production and Na-dependent Pi transport. Am J Physiol 255: F957-F961
Caverzasio J, Rizzoli R, Martin TJ, Bonjour J-P (1988) Tumoral synthetic parathyroid hormone-related peptide inhibits amiloridesensitive sodium transport in culture renal epithelia. Pflugers Arch 413: 96–98
Pizurki L, Rizzoli R, Bonjour J-P (1990) Inhibition by (D-Trp12, Tyr34) bPTH(7-34) amide of PTH and PTHrP effects on Pi transport in renal cells. Am J Physiol 259: F389-F392
Yates AJP, Guiterrez GE, Smolens P, Travis PS, Katz MS, Audemorte TB, Boyce BF, Hymer TK, Poser JW, Mundy GR (1988) Effects of a synthetic peptide of a parathyroid hormone-related protein on calcium homeostasis, renal tubular calcium absorption and bone metabolism in vivo and in vitro in rodents. J Clin Invest 81: 932–938
Rizzoli R, Caverzasio J, Chapuy MC, Martin TJ, Bonjour J-P (1989) Role of bone and kidney in parathyroid hormone-related peptide-induced hypercalcemia in rats. J Bone Miner Res 4: 759–765
Zhou H, Leaver DD, Moseley JM, Kemp B, Ebeling PR, Martin TJ (1989) Actions of parathyroid hormone-related protein on the rat kidney in vivo. J Endocrinol 122: 229–235
Buchs B, Rizzoli R, Bonjour J-P (1991) Evaluation of bone resorption and renal tubular reabsorption of calcium and phosphate in malignant and nonmalignant hypercalcemia. Bone 12: 47–56
Pizurki L, Rizzoli R, Caverzasio J, Bonjour J-P (1990) Effect of transforming growth factor-α and parathyroid hormone-related protein on phosphate transport in renal cells. Am J Physiol 259: F929-F935
Law F, Rizzoli R, Bonjour J-P (1993) Transforming growth factor-β modulates the parathyroid hormone-related protein-induced responses in renal epithelial cells. Endocrinology 133: 145–151
Davicco MJ, Coxam V, Lefaivre J, Barlet JP (1992) Parathyroid hormone-related peptide increases urinary phosphate excretion in fetal lambs. Exp Physiol 77: 377–383
Winquist RJ, Baskin EP, Vlasuk GP (1987) Synthetic tumor-derived human hypercalcemic factor exhibits parathyroid hormone-like vasorelaxation in renal arteries. Biochem Biophys Res Commun 149: 227–232
Silve CM, Hradek GT, Jones AL, Arnaud CD (1982) Parathyroid hormone receptor in intact embryonic chicken bone: characterization and cellullar localization. J Cell Biol 94: 379–386
Rizzoli R, Somerman M, Murray TM, Aurbach GD (1983) Binding of radioiodinated parathyroid hormone to clone bone cells. Endocrinology 113: 1832–1838
Pizurki L, Rizzoli R, Caverzasio J, Bonjour J-P (1991) Stimulation by parathyroid hormone-related protein and transforming growth factor-α of phosphate transport in osteoblast-like cells. J Bone Miner Res 6: 1235–1241
Civitelli R, Martin TJ, Fausto A, Gunsten SL, Hruska KA, Avioli LV (1989) Parathyroid hormone-related peptide transiently increase cytosolic calcium in osteoblast-like cells: comparison with parathyroid hormone. Endocrinology 125: 1204–1210
Stewart AF, Mangin M, Wu T, Goumas D, Insogna KL, Burtis WJ, Broadus AE (1988) Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats. J Clin Invest 81: 596–600
McSheehy PM, Chambers TJ (1986) Osteoblastic cells mediate osteoclastic responsiveness to parathyroid hormone. Endoccrinology 118: 824–828
MacDonald BR, Takahashi N, McManus LM, Holahan J, Mundy GR, Roodman GD (1987) Formation of multinucleated cells that respond to osteotropic hormones in long term human bone marrow cultures. Endocrinology 120: 2326–2333
Akatsu T, Takahashi N, Udagawa N, Sato K, Nagata N, Moseley JM, Martin TJ, Suda T (1989) Parathyroid hormone (PTH)-related protein is a potent stimulator of osteoclast-like multinucleated cell formation to the same extents as PTH in mouse marrow cultures. Endocrinology 125: 20–27
Evely RS, Bonomo A, Schneider H-G, Moseley JM, Gallagher J, Martin TJ (1991) Structural requirements for the action of parathyroid hormone-related protein (PTHrP) on bone resorption by isolated osteoclasts. J Bone Miner Res 6: 85–93
Fenton AJ, Kemp BE, Hammonds RG, Mitchelhill K, Moseley JM, Martin TJ, Nicholson GC (1991) A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein: PTHrP(107-111). Endocrinology 129: 3424–3426
Abbas SK, Pickard DW, Illingworth D, Storer J, Purdie DW, Moniz C, Dixit M, Caple IW, Ebeling PR, Rodda CP, Martin TJ, Care AD (1990) Measurement of parathyroid hormone-related protein in extract of foetal parathyroid glands and placental membranes. J Endocrinol 124: 319–325
Zajac JD Callaghan J, Eldridge C, Diefenbach-Jagger H, Suva LJ, Hudson P, Moseley JM, Michelangeli VP, Pasquini G (1989) Production of parathyroid hormone-related protein by a rat parathyroid cell line. Mol Cell Endocrinol 67: 107–112
Burton PBJ, Moniz C, Quirke P, Tzannatos C, Pickles A, Dixit M, Triffit JT, Jüeppner H, Segre GV, Knight DE (1990) Parathyroid hormone-related peptide in the human fetal uro-genital tract. Mol Cell Endocrinol 69: R13-R17
Senior PV, Heath DA, Beck F (1991) Expression of parathyroid hormone-related protein mRNA in the rat before birth: demonstration by hybridization histochemistry. J Mol Endocrinol 6: 281–290
Nijs-De Wolf N, Pepersack T, Corvilain J, Karmali R, Bergmann P (1991) Adenylate cyclase stimulating activity immunologically similar to parathyroid hormone-related peptide can be extracted from fetal long bones. J Bone Miner Res 6: 921
Borget LJ, Plass ED (1923) Placental transmission. I. The calcium and magnesium content of foetal and maternal blood serum. J Biol Chem 56: 297–307
Allgrove J, Adamia S, Manning RM, O'Riordan JL (1985) Cutobiochemical assay of parathyroid hormone in maternal and cord blood Arch Dis Child 60: 110–115
Care AD, Caple IW, Abbas SK, Pickard DW (1986) The effect of fetal thyroparathyroidectomy on the transport of calcium across the ovine placenta to the fetus. Placenta 7: 417–424
Abbas SK, Pickard DW, Rodda CP, Heath JA, Hammonds RG, Wood WI, Caple IW, Martin TJ, Care AD (1989) Stimulation of ovine placental calcium transport by purified natural and recombinant parathyroid hormone-related protein (PTHrP) preparations. Q J Exp Physiol 74: 549–552
Barlet JP, Davicco M-J, Coxam V (1990) Synthetic parathyroid hormone-related peptide (1–34) fragments stimulates placental calcium transfer in ewes. J Endocrinol 127: 33–37
Care AD, Abbas SK, Pickard DW, Barri M, Drinkhill M, Findlay JBC, White IR, Caple IW (1990) Stimulation of ovine placental transport of calcium and magnesium by mid-molecule fragments of human parathyroid hormone-related protein. Exp Physiol 75: 605–608
Barri M, Abbas SK, Pickard DW, Hammonds RG, Wood WI, Caple IW, Martin TJ, Care AD (1990) Fetal magnesium homeostasis in the sheep. Exp Physiol 75: 681–688
MacIsaac RJ, Heath JA, Rodda CP, Moseley JM, Care AD, Martin TJ, Caple IW (1991) Role of fetal parathyroid glands and parathyroid hormone-related protein in the regulation of placental transport of calcium, magnesium and inorganic phosphate. Reprod Fertil Dev 3: 447–456
Thiede MA (1989) The mRNA encoding a parathyroid hormone-like peptide is produced in mammary tissue in response to elevations in serum prolactin. Mol Endocrinol 3: 1443–1447
Thurston AW, Cole JA, Hillman LS, Im JH, Thorne PK, Krause WJ, Jones JR, Eber SL, Forte LR (1990) Purification and properties of parathyroid hormone-related peptide isolated from milk. Endocrinology 126: 472–479
Ratcliffe WA, Green E, Emly J, Norbury S, Lindsay M, Heath DA, Ratcliffe JG (1990) Identification and partial characterization of parathyroid hormone-related protein in human and bovine milk. J Endocrinol 127: 2179–2182
Law FMK, Moate PJ, Leaver DD, Diefenbach-Jagger H, Grill V, Ho PWM, Martin TJ (1991) Parathyroid hormone-related protein in milk and its correlation with bovine milk calcium. J Endocrinol 128: 21–26
Ferrari SL, Rizzoli R, Bonjour J-P (1992) Parathyroid hormone-related protein production by primary cultures of mammary epithelial cells. J Cell Physiol 150: 304–311
Ratcliffe WA, Thompson GE, Care AD, Peaker M (1992) Production of parathyroid hormone-related protein by the mammary gland of the goat. J Endocrinol 133: 87–93
Thiede MA, Grasser WA, Peterson DN (1992) Regulated expression of parathyroid hormone-related protein in mammary blood supply supports a role in mammary blood flow. Bone Miner 17 [Suppl 1]: 71
Moser PB, Reynolds R, Acharya S, Howard MP, Audon MB (1988) Calcium and magnesium dietary intakes and plasma and milk concentrations of Nepalese lactating women. Am J Clin Nutr 47: 735–739
Barlet JP (1974) Role physiologique de la calcitonine chez la chevre gestante ou allaitante. Ann Biol Anim Bioch Biophys 14: 447–457
Garner SC, Boass A, Toverud SU (1990) Parathyroid hormone is not required for normal milk composition or secretion or lactation-associated bone loss in normocalcemic rats. J Bone Miner Res 5: 69–75
Saunders TJ, Opperman LA, Gorman J, Bruns DE, Bruns ME (1990) Tissue distribution of vitamin D receptor (VDR) mRNA in mice and rats and its control during reproduction. J Bone Miner Res 5 [Suppl 2]: S263
Goff JP, Reinhardt TA, Lee S, Hollis BW (1991) Parathyroid hormone-related peptide content of bovine milk and calf blood assessed by radioimmunoassay and bioassay. Endocrinology 129: 2815–2819
Yamamoto M, Fisher JE, Thiede MA, Caulfield MP, Rosenblatt M, Duong Le T (1992) Concentrations of parathyroid hormone-related protein in rat milk change with duration of lactation and interval from previous suckling, but not with milk calcium. Endocrinology 130: 741–747
Barlet JP, Champredon C, Coxam V, Davicco MJ, Tressol JC (1992) Parathyroid hormone-related peptide might stimulate calcium secretion into the milk of goats. J Endocrinol 132: 353–359
Zhou LX, Nemere I, Norman A (1992) A parathyroid hormone-related peptide induces transcaltachia (the rapid, hormonal stimulation of intestinal Ca2+ transport). Biochem Biophys Res Commun 186: 69–73
Yamamoto Y, Fukase M, Fujii Y, Fujita T (1989) The effects of human parathyroid hormone-related peptide on cytosolic free calcium and cAMP production in opossum kidney cells. Bone Miner 7: 221–231
Rizzoli R, Arlot M, Caverzasio J, Meunier P, Bonjour JP (1989) Blunted stimulation of bone formation (BF) in parathyroid hormone-related protein(PTHrP)-infused thyroparathyroidectomized (TPTX) rats. J Bone Miner Res 4 [Suppl 1]: A592
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Law, F., Ferrari, S., Rizzoli, R. et al. Parathyroid hormone-related protein and calcium phosphate metabolism. Pediatr Nephrol 7, 827–833 (1993). https://doi.org/10.1007/BF01213369
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DOI: https://doi.org/10.1007/BF01213369