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Expert Opinion on Investigational Drugs Volume 9, 2000 - Issue 6
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Review

The parathyroid hormone, its fragments and analogues - potent bone-builders for treating osteoporosis

James Whitfield Institute for Biological Sciences, National Research Council of Canada, Bldg. M-54, Montreal Road Campus, Ottawa, ON, Canada K1A 0R6. [email protected]
,
Paul Morley Institute for Biological Sciences, National Research Council of Canada, Bldg. M-54, Montreal Road Campus, Ottawa, ON, Canada K1A 0R6. [email protected]
&
Gordon Willick Institute for Biological Sciences, National Research Council of Canada, Bldg. M-54, Montreal Road Campus, Ottawa, ON, Canada K1A 0R6. [email protected]
Pages 1293-1315 | Published online: 24 Feb 2005

Bibliography

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  • ••An excellent summary of the roles of RANK, RANKL andosteoprotegerin in the control of osteoblast generation and activity.
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  • MANOLAGAS SC, WEINSTEIN RS, BELLIDO T et al.: Activa-tors of non-genomic estrogen-like signaling (ANGELS): a novel class of small molecules with bone anabolic properties. J. Bone Miner. Res. (1999) 14:S180.
  • ••An abstract that summarises the PTH-like osteogenic actionof the ANGELS oestrogen analogues.
  • FLEISCH H: Bisphosphonates in Bone Disease. The Parthenon Publishing Group, London, UK (1997).
  • FLEISCH H: Bisphosphonates: mechanisms of action. Endocrine Rev. (1998) 19:80–100.
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  • SELYE H: On the stimulation of new bone formation with parathyroid extract and irradiated ergosterol. Endocrinology (1932) 16:547-558. The start of it all! The first definitive demonstration of PTH's osteogenic action in rat pups.
  • MORLEY P, WHITFIELD JF, WILLICK GE: Design and applications of parathyroid hormone analogues. Curr. Med. Chem. (1999) 6:1095–1106.
  • YAMAGUCHI T, CHATTOPADHYAY N, BROWN EH: G protein-coupled Ca2±(Ca2+o)-sensing receptor (CaR): roles in cell signaling and control of diverse cellular functions. Adv. Pharmacol. (2000) 47:209–253.
  • MANNSTADT M, JUPPNER H, GARDELLA TJ: Receptors for PTH and PTHrP: their biological importance and functional properties. Am. J. Physiol. (1999) 277:F665–675.
  • DUNCAN EL, BROWN EL, SINSHEIMER J et al.: Suggestive linkage of the parathyroid receptor Type 1 to osteopo-rosis. J. Bone Miner. Res. (1999) 14:1993–1999.
  • FLOWER DR: Modeling G-protein-coupled receptors for drug design. Biochim. Biophys. Acta (1999) 1422:207–234.
  • JOUISHOMME H. WHITFIELD JF, CHAKRAVARTHY BR,et al.: The protein kinase-C activation domain of the parathyroid hormone. Endocrinology (1992) 130:53–60.
  • ••The first attempt to locate and separate the two differentsignaling regions of the PTH molecule.
  • JOUISHOMME H, WHITFIELD JF, GAGNON L et al.: Further definition of the protein kinase C activation domain of the parathyroid hormone./ BoneMiner. Res. (1994) 9:943–949.
  • WHITFIELD JF, MORLEY P, WILLICK G et al.: Stimulationof the growth of femoral trabecular bone in ovariecto-mized rats by the novel parathyroid hormone fragment IIPTH-(1-31)NH2 (ostabolin). Calcy: Tissue Int. (1996) 58:81–87.
  • WHITFIELD JF, MORLEY P, WILLICK G et al.: Cyclizationby a specific lactam increases the ability of human parathyroid hormone IIPTH-(1-31)NH2 to stimulate bone growth in ovariectomized rats. J. Bone Miner. Res. (1997) 12:1246–1252.
  • WHITFIELD JF, ISAACS RJ, MACLEAN S et al.: Stimulation of membrane-associated protein kinase-C activity in spleen lymphocytes by IIPTH-(1-31)NH2, its lactam derivative, [Leu2I-cyclo(G1u22-Lys26)-1213TH-(1-31)NH2 and hPH-(1-30)NH2. Cell. Signal. (1999) 11:159–164.
  • ARMAMENTO-VILLAREAL R, ZIAMBARAS K, ABBASI-JARHOMI SH, et al.: An intact N terminus is required for the anabolic action of parathyroid hormone on adult rats. J. Bone Miner. Res. (1997) 12:384–392.
  • RIXON RH, WHITFIELD JF, GAGNON L et al.: Parathyroid hormone fragments may stimulate bone growth in ovariectomized rats by activating adenylyl cyclase. J. Bone Miner. Res. (1994) 9:1179–1189.
  • ••The first demonstration that adenyl cyclase stimulation is thesine qua non for PTH's ostegenic action in rat bones.
  • STREIN K: Are animal studies with bisphosphonates and PTH fragments predictive for the clinical situation? In: Bone Diseases and Osteoporosis. Russell RG (Ed.) IBC Technical Services Limited, London, UK (1994):Article 12.
  • DONAHUE HJ, FRYER MJ, ERIKSEN EF et al.: Differential effects of parathyroid hormone and its analogues on cytosolic calcium ions and cAMP levels in cultured rat osteoblast-like cells. J. Biol. Chem. (1988) 263:13522–13527.
  • FUJIMORI A, CHENG SL, AVIOLI LV et al.: Structure- function relationship of parathyroid hormone: activa-tion of phospholipase-C, protein kinase-A and -C in osteosarcoma cells. Endocrinology (1992) 130:29–36.
  • ••The second published attempt to locate and separate thetwo principal signaling regions of PTH.
  • AZARANI A, GOLTZMAN D, ORLOWSKI J et al.: Structurally diverse N-terminal peptides of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) inhibit the Neill+ exchanger NH3 isoforra by binding to the PTH/PTHrP receptor Type I and activating distinct signaling pathways. J. Biol. Chem. (1996) 271:14931–14936.
  • FRIEDMAN PA, GESEK FA, MORLEY P et al.: Cell-specificsignaling and structure-activity relations of parathy-roid hormone analogs in mouse kidney cells. Endocri-nology (1999) 140:301–309.
  • RIHANI-BISHARAT S, MAOR G, LEWINSON D: In vivo anabolic effects of parathyroid hormone (PTH) 28-48 and N-terminal fragments of PTH and PTH-related protein on neonatal mouse bones. Endocrinology (1998) 139:974–981.
  • AZARANI A, GOLTZMAN D, ORLOWSKI J: Parathyroidhormone and parathyroid hormone-related peptide inhibit the apical Na/11+ exchanger NHE-3 isoform in renal cells (OK) via a dual signaling cascade involving protein kinase A and C. J. Biol. Chem. (1995) 270:20004–20010.
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  • LICHONG KP, LI DY, ORLOWSKI D et al.: Selectivedomains of PTH and PTHrP activate the protein kinase C pathways and differentially influence the Neill+ (NHE3) and the Type II Na/Pi co-transporter. Bone (1998) 23:S356.
  • TAKASU H, BRINGHURST FR: Type-1 parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptors activate phospholipase C in response to carboxyl-truncated analogs of PTH. Endocrinology (1998) 139:4293–4299.
  • TAKASU H, GUO J, BRINGHURST FR: Dual signaling andligand selectivity of the human PTH/PTHrP receptor. J. Bone Miner. Res. (1999) 14:11–20.
  • TAKASU H, GARDELLA TJ, LUCK MD et al.: Amino-terminal modifications of human parathyroid hormone (PTH) selectively alter phospholipase C signaling via the Type 1 receptor: implications for design of signal-specific PTH ligands. Biochemistry (1999) 38:13453–13460.
  • WHITFIELD JF, ISAACS RJ, CHAKRAVARTHY B et al Stimulation of protein kinase-C activity in cells expressing human parathyroid hormone (PTH) receptors by C- and N-terminally truncated fragments of 13111-(1–34). (Submitted)
  • KOH AJ, BEECHER CA, ROSOL TJ et al.: 3', 5'-Cyclicadenosine monophosphate activation in osteoblastic cells: effect on parathyroid hormone-1 receptor and osteoblastic differentiation. Endocrinology (1999) 140:3154–3161.
  • BAUER E, AUB JC, ALBRIGHT F: Studies of calcium andphosphorus Metabolism : V. a study of the bone trabeculae as a readily available reserve supply of calcium. J. Exp. Med. (1929) 49:145-162. Contains the first glimpse of PTH's osteogenic action.
  • DEMPSTER DW, COSMAN F, PARISIEN M et al.: Anabolicaction of parathyroid hormone. Endocrine Rev. (1993) 14:690–709.
  • BROMMAGE R, HOTCHKISS CE, LEES CJ et al.: Daily treatment with human recombinant parathyroid hormone -(1-34), LY33333, for 1 year increases bone mass in ovariectomized monkeys. J. Clin. Endocrinol. Metab. (1999) 84:3757–3763.
  • COSMAN F, LINDSAY R: Parathyroid hormone as anabolic treatment. In: Osteoporosis. Stevenson JC, Lindsay R (Ed.). Chapman & Hall, London, UK (1998):293–307.
  • DEMPSTER DW: The contribution of trabecular architectural to cancellous bone quality. J. Bone Miner. Res. (2000) 15:20–23.
  • HOCK JM: Stemming bone loss by suppressing apoptosis. J. Clin. Invest. (1999) 104:371–373.
  • HODSMAN AB, DROST D, FRAHER LJ et al.: The additionof a raloxifene analog (LY117018) allows for reduced PTH(1-34) dosing during reversal of osteopenia in ovariectomized rats. J. Bone Miner. Res. (1999) 14:675–679.
  • HODSMAN AB, WATSON PH, DROST D et al.: Assessmentof maintenance therapy with reduced doses of PTH(1-34) in combination with a raloxifene analogue (LY117018) following anabolic therapy in the ovariec-tomized rat. Bone (1999) 24:451–455.
  • JEROME CP, JOHNSON CS, VAFAI HT et al.: Effect of treatment for 6 months with human parathyroid hormone (1-34) peptide in ovariectomized cynomolgus monkeys (Macaca fascicularis). Bone (1999) 25:301–309.
  • JILKA RL, WEINSTEIN RS, BELLIDO T et al.: Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J. Clin. Invest. (1999) 104:439–446.
  • ••This paper reports the results of experiments, which suggestthat PTH stimulates bone growth by preventing apoptosis and thus extending the working lifespan of osteoblasts.
  • LIANG JD, HOCK JM, SANDUSKY GE et al.: Immunohisto-chemical localization of selected early response genes expressed in trabecular bone of young rat given PTH 1-34. Calcff. Tissue Int. (1999) 65:369–373.
  • MOHAN S, KUTILEK S, ZHANG C et al.: Evidence of PTH effects on bone formation may involve modulation of PKA pathway while its effects on bone resorption may involve modulation of PKC pathway in a mouse model. Bone (1998) 23:S449.
  • ••This long and very important abstract summarises the resultsof experiments on mice which indicate that the 'mini-PTH', hPTH-(1–31)NH2, is as strong a stimulator of adenyl cyclase as hPTH-(1–34), but a much weaker stimulator of osteoclast activity than hPTH-(1–34).
  • MOSEKILDE L: Osteoporosis: mechanisms and models.In: Anabolic Treatments for Osteoporosis. Whitfield JF, Morley P (Ed.), CRC Press, Boca Raton, USA (1997):31–58.
  • MOSEKILDE L, THOMSEN JS, MCOSKER JE: No loss ofbiomechanical effects after withdrawal of short-term PM treatment in an aged, osteopenic, ovariectomized rat model. Bone (1997) 20:429–437.
  • OPAS EE, GENTILE MA, ROSSERT JA et al.: Parathyroidhormone and prostaglandin E2 preferentially increase luciferase levels in bone of mice harboring a luciferase transgene controlled by elements of the pro-al(I) collagen promoter. Bone (2000) 27:27–32.
  • SOGAARD CH, MOSEKILDE L, THOMSEN JS et al.: Acomparison of the effects of two anabolic agents (fluoride and PTH) on ash density and bone strength assessed in an osteopenic rat model. Bone (1997) 20:439–449.
  • SUNG WL, CHAN BS, LUK CK et al.: High-yield expres-sion of fully bioactive N-terminal parathyroid hormone in Escbericbia cok. JUBMB Life (2000) 5:(In press).
  • TAM CS, HEERSCHE JN, MURRAY TM et al.: Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration. Endocrinology (1982) 110:506–512.
  • ••The first clear demonstration that intermittent injection isnecessary for PTH's osteogenic action.
  • TOROMANOFF A, AMMANN P, MOSEKILDE L et al.: Parathyroid hormone increases bone formation and improves mineral balance in vitamin D-deficient female rats. Endocrinology (1997) 138:2449–2457.
  • WALKER D: The induction of osteopetrotic changes in hypophysectomized, thyroparathyroidectomized and intact rats of various ages. Endocrinology (1971) 89:1389–1406.
  • ••The proof that it is PTH rather than calcitonin that stimulatesbone formation in PTH-treated rats and that PTH's osteogenic potency is inversely proportional to a rat's age.
  • WHITFIELD JF, MORLEY P, FRAHER L et al.: The stimula-tion of vertebral and tibial bone growth by the parathyroid hormone fragments, IIPTH-(1-31)N112, [Leu27]cyclo(G1u22-Lys26)hPTH-(1-31)N112 and IIPTH-(1-30)NH2. Calcff. Tissue Int. (2000) 66:307–312.
  • WHITFIELD JF, MORLEY P, WILLICK GE et al.: Lactam formation increases receptor binding, adenylyl cyclase stimulation and bone growth stimulation by human parathyroid hormone (hPTH)-(1-28)N112. J. Bone Miner. Res. (2000) 15:964–970.
  • ••A dramatic demonstration of how the very low receptoraffinity and the adenyl cyclase-stimulating and osteogenic activities of a small PTH fragment can be raised nearly to the level of the potent large peptides.
  • WRONSKY TJ, LI M: Pin skeletal effects in the ovariec-tomized rat model for postmenopausal bone loss. In: anabolic Treatments for Osteoporosis. Whitfield JF, Morley P (Ed.). CRC Press Boca Raton, USA (1997):59–81.
  • FERMORE B, SKERRY TM: PTWP"MrP receptor expres-sion on osteoblasts and osteocytes but not resorbing bone surfaces in growing rats. J. Bone Miner. Res. (1995) 10:1935–1943.
  • LANE NE, THOMPSON JM, STREWLER GJ et al.: Intermit-tent treatment with parathyroid hormone (1113TH 1-34)increased trabecular bone volume but not connectivity in osteopenic rats. J. Bone Miner. Res. (1995) 10:1470–1477.
  • WHITFIELD JF, MORLEY P, WILLICK G et al.: Comparison of the abilities of human parathyroid hormone (hPTH)-(1-34)and[Leu27]-cyclo(G1u22-Lys26)-hPTH-(1-31)NH2 to stimulate femoral trabecular bone growth in ovariectomized rats. Calcif. Tissue Int. (1998) 63:423–428.
  • BOYCE RW, PADDOCK CL, FRANKS AF et al.: Effects of intermittent hPTH-(1–34) alone and in combination with 1, 25(OH)2D3 or residronate on endosteal bone remodelling in canine cancellous and cortical bone./ Bone Miner. Res. (1996) 11:600–613.
  • DELMAS PD, VERGNAUD P, ARLOT ME et al.: The anabolic effect of human PTH (1–34) on bone formation is blunted when bone resorption is inhibited by the bisphosphonate tiludronate_Is activated resorption a prerequisite for the in vivo effect of PTH on formation in a remodelins system? Bone (1995) 16:603–610.
  • ANDREASSEN TT, EJERSTED C, OXLUND H: Intermittent parathyroid hormone (1-34) treatment increases callus formation and mechanical strength of healing rat fractures. J. Bone Miner. Res. (1999) 14:960–968.
  • ••The first definitive demonstration of the ability of sc.injections of hPTH-(1–34) to heal fractures in rats.
  • BONADIO J, SMILEY E, PATH P et al.: Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration. Nature Medicine (1999) 5:753–759.
  • ••A recipe for healing severe fractures in beagles and rats byimplanting into the break a collagen matrix containing a plasmid carrying the gene for hPTH-that when picked up by a callus fibroblast causes the cell to make PTH that greatly accelerates fracture healing.
  • FANG J, ZHU YY, SMILEY E et al.: Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc. Natl. Acad. Sci. USA (1996) 93:5753–5758.
  • ••The first report of the fracture-healing potency of collagenmatrices (GAMs) containing a plasmid carrying the gene for hPTH-(1–34).
  • GOLDSTEIN SA, BONADIO J: Potential role for direct gene transfer in the enhancement of fracture healing. Clin. Ortbop. (1998) 355 (Suppl.):S154–S162.
  • GALLIEN-LARTIGUE O, CARREZ D: Induction in vitro de la phases dans les cellules souches muhipotentes de la moelle osseuse par l'hormone parathyroVdienne. C.R. Acad. Sci. Paris(1974) 278:1765–1768.
  • PERRIS AD, MACMANUS JP, WHITFIELD JF, WEISS LA: Parathyroid glands and mitotic stimulation in rat bone marrow after hemorrhage. Am. J. Physiol. (1971) 220:773–778.
  • KANATANI M, SUGIMOTO T, TAKAHASHI Y et al.: Estrogen via the estrogen receptor blocks cAMP-mediated parathyroid hormone (PTH)-stimulated osteoclast function./ Bone Miner. Res. (1998) 13:854–862.
  • BIANCO P, RIMINUCCI M, KUZNETSOV S, ROBEY PG: Muhipotential cells in the bone marrow stroma: regulation in the context of organ physiology. Crit. Revs. Euk. Gene Express. (1999) 9:159–173.
  • ••An up-to-date discussion of the functions of marrow stromalosteoblastic cells.
  • AMIZUKA N, KARAPLIS AC, HENDERSON JE et al.: Haploinsufficiency of parathyroid hormone related peptide (PTHrP) results in abnormal postnatal development. Dev. Biol. (1996) 175:166–176.
  • KARTSOGIANNIS V, MOSELEY J, MCKELVIE B et al.: Temporal expression of PTHrP during endochondral bone formation in mouse and intramembranous bone formation in an in vivo rabbit model. Bone (1997) 21:385–392.
  • WALSH CA, BOWLER WB, BILBE G et al.: Effects of P'M on PTHrP gene expression in human osteoblasts: upregulation with the kinetics of an immediate early gene. Biochem. Biophys. Res. Commun. (1997) 239:155–159.
  • AMLING M, NEFF L, TANAKA S et al.: Bc1-2 lies downstream of parathyroid hormone-related peptide in a signaling pathway that regulates chondrocyte maturation during skeletal development. J. Cell Biol. (1997) 136:205–213.
  • LAM MH, HOUSE CM, TIGANIS T et al.: Phosphorylation at the cyclin- dependent kinase site (Thr 85) of parathyroid hormone-related protein negatively regulates its nuclear localization. J. Biol. Chem. (1999) 274:18559–18566.
  • AARTS MM, RIX A, GUO J et al.: The nucleolar targeting signal (NTS) of parathyroid hormone-related protein mediates endocytosis and nucleolar translocation. J. Bone Miner. Res. (1999) 14:1493–14503.
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Websites

  • http://courses.washington.edu/bonephys/ OTT S: Osteoporosis. .
  • •Contains vivid animations of BMUs in normal and osteoporotic bones.
  • http://www.medscape.com MANOLAGAS SC: Advances in the treatment of osteoporosis. Medscape
  • ••Endocrinology Journal (1999) 1, n 10, A summary of the1999 meeting of the American Society for Bone and Mineral Research in St. Louis, USA that focuses on the osteogenic actions of PTH and novel oestrogen analogs, the ANGELS.

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