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Physiol. Rev. 76: 127-173, 1996;
0031-9333/96 $15.00
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Physiological Reviews, Vol 76, 127-173, Copyright © 1996 by American Physiological Society

JOURNAL ARTICLE

Defining the roles of parathyroid hormone-related protein in normal physiology

W. M. Philbrick, J. J. Wysolmerski, S. Galbraith, E. Holt, J. J. Orloff, K. H. Yang, R. C. Vasavada, E. C. Weir, A. E. Broadus and A. F. Stewart
Division of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, USA.

Parathyroid hormone-related protein (PTHrP) was discovered as a result of a search for the circulating factor secreted by cancers which causes the common paraneoplastic syndrome humoral hypercalcemia of malignancy. Since the identification of the peptide in 1982 and the cloning of the cDNA in 1987, it has become clear that PTHrP is a prohormone that is posttranslationally cleaved by prohormone convertases to yield a complex family of peptides, each of which is believed to have its own receptor. It is also clear that the PTHrP gene is expressed not only in cancers but also in the vast majority of normal tissues during adult and/or fetal life. In contrast to the situation in humoral hypercalcemia of malignancy in which PTHrP plays the role of a classical "endocrine" hormone, under normal circumstances PTHrP plays predominantly paracrine and/or autocrine roles. These apparent physiological functions are also complex and appear to include 1) regulation of smooth muscle (vascular, intestinal, uterine, bladder) tone, 2) regulation of transepithelial (renal, placental, oviduct, mammary gland) calcium transport, and 3) regulation of tissue and organ development, differentiation, and proliferation. In this review, the discovery of PTHrP, the structure of its gene and its cDNAs, and the posttranslational processing of the initial translation products are briefly reviewed. Attention is then focused on a detailed organ system-oriented review of the normal physiological functions of PTHrP.


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P. ESBRIT, M. V. ALVAREZ-ARROYO, F. DE MIGUEL, O. MARTIN, M. E. MARTINEZ, and C. CARAMELO
C-Terminal Parathyroid Hormone-Related Protein Increases Vascular Endothelial Growth Factor in Human Osteoblastic Cells
J. Am. Soc. Nephrol., June 1, 2000; 11(6): 1085 - 1092.
[Abstract] [Full Text]

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 EndocrinologyHome page
M. Falzon and P. Du
Enhanced Growth of MCF-7 Breast Cancer Cells Overexpressing Parathyroid Hormone-Related Peptide
Endocrinology, May 1, 2000; 141(5): 1882 - 1892.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
M. I. Ramirez, U.-I. Chung, and M. C. Williams
Aquaporin-5 Expression, but Not Other Peripheral Lung Marker Genes, Is Reduced in PTH/PTHrP Receptor Null Mutant Fetal Mice
Am. J. Respir. Cell Mol. Biol., March 1, 2000; 22(3): 367 - 372.
[Abstract] [Full Text]

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 Biol. Reprod.Home page
J. C. Garmey, J. A. Schnorr, M. E. Bruns, D. E. Bruns, R. M. Seaner, J. E. Ferguson II, F. C. Luking Jayes, C. Aguirre, and J. D. Veldhuis
Expression of Parathyroid Hormone-Related Peptide (PTH-rp) and Its Receptorin the Porcine Ovary: Regulation by Transforming Growth Factor-{beta} and Possible Paracrine Effects of Granulosa Cell PTH-rp Secretion on Theca Cells
Biol Reprod, February 1, 2000; 62(2): 334 - 339.
[Abstract] [Full Text]

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 Cancer Res.Home page
K. M. Dougherty, E. A. G. Blomme, A. J. Koh, J. E. Henderson, K. J. Pienta, T. J. Rosol, and L. K. McCauley
Parathyroid Hormone-related Protein as a Growth Regulator of Prostate Carcinoma
Cancer Res., December 1, 1999; 59(23): 6015 - 6022.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
R. J. Bosch, P. Rojo-Linares, G. Torrecillas-Casamayor, M. C. Iglesias-Cruz, D. Rodriguez-Puyol, and M. Rodriguez-Puyol
Effects of parathyroid hormone-related protein on human mesangial cells in culture
Am J Physiol Endocrinol Metab, December 1, 1999; 277(6): E990 - E995.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
H. Lang, N. Endlich, V. Lindner, K. Endlich, T. Massfelder, A. F. Stewart, C. Saussine, and J.-J. Helwig
Parathyroid Hormone-Related Protein in Rat Penis: Expression, Localization, and Effect on Cavernosal Pressure
Endocrinology, September 1, 1999; 140(9): 4342 - 4350.
[Abstract] [Full Text]

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 EndocrinologyHome page
T. B. Usdin, J. Hilton, T. Vertesi, G. Harta, G. Segre, and E. Mezey
Distribution of the Parathyroid Hormone 2 Receptor in Rat: Immunolocalization Reveals Expression by Several Endocrine Cells
Endocrinology, July 1, 1999; 140(7): 3363 - 3371.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
M. H. C. Lam, C. M. House, T. Tiganis, K. I. Mitchelhill, B. Sarcevic, A. Cures, R. Ramsay, B. E. Kemp, T. J. Martin, and M. T. Gillespie
Phosphorylation at the Cyclin-dependent Kinases Site (Thr85) of Parathyroid Hormone-related Protein Negatively Regulates Its Nuclear Localization
J. Biol. Chem., June 25, 1999; 274(26): 18559 - 18566.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
R. L. Sutliff, C. S. Weber, J. Qian, M. L. Miller, T. L. Clemens, and R. J. Paul
Vasorelaxant Properties of Parathyroid Hormone-Related Protein in the Mouse: Evidence for Endothelium Involvement Independent of Nitric Oxide Formation
Endocrinology, May 1, 1999; 140(5): 2077 - 2083.
[Abstract] [Full Text]

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 EndocrinologyHome page
T. Massfelder and J.-J. Helwig
Editorial: Parathyroid Hormone-Related Protein in Cardiovascular Development and Blood Pressure Regulation
Endocrinology, April 1, 1999; 140(4): 1507 - 1510.
[Full Text]

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 EndocrinologyHome page
S. Maeda, R. L. Sutliff, J. Qian, J. N. Lorenz, J. Wang, H. Tang, T. Nakayama, C. Weber, D. Witte, A. R. Strauch, et al.
Targeted Overexpression of Parathyroid Hormone-Related Protein (PTHrP) to Vascular Smooth Muscle in Transgenic Mice Lowers Blood Pressure and Alters Vascular Contractility
Endocrinology, April 1, 1999; 140(4): 1815 - 1825.
[Abstract] [Full Text]

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 EndocrinologyHome page
J. Qian, J. N. Lorenz, S. Maeda, R. L. Sutliff, C. Weber, T. Nakayama, M. C. Colbert, R. J. Paul, J. A. Fagin, and T. L. Clemens
Reduced Blood Pressure and Increased Sensitivity of the Vasculature to Parathyroid Hormone-Related Protein (PTHrP) in Transgenic Mice Overexpressing the PTH/PTHrP Receptor in Vascular Smooth Muscle
Endocrinology, April 1, 1999; 140(4): 1826 - 1833.
[Abstract] [Full Text]

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 J. Am. Soc. Nephrol.Home page
F. DE MIGUEL, P. MARTINEZ-FERNANDEZ, C. GUILLEN, A. VALIN, A. RODRIGO, M. E. MARTINEZ, and P. ESBRIT
Parathyroid Hormone-Related Protein (107-139) Stimulates Interleukin-6 Expression in Human Osteoblastic Cells
J. Am. Soc. Nephrol., April 1, 1999; 10(4): 796 - 803.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
M. H. C. Lam, L. J. Briggs, W. Hu, T. J. Martin, M. T. Gillespie, and D. A. Jans
Importin beta  Recognizes Parathyroid Hormone-related Protein with High Affinity and Mediates Its Nuclear Import in the Absence of Importin alpha
J. Biol. Chem., March 12, 1999; 274(11): 7391 - 7398.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
M. L. Brines and A. E. Broadus
Parathyroid Hormone-Related Protein Markedly Potentiates Depolarization-Induced Catecholamine Release in PC12 Cells via L-Type Voltage-Sensitive Ca2+ Channels
Endocrinology, February 1, 1999; 140(2): 646 - 651.
[Abstract] [Full Text]

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 DevelopmentHome page
M. Dunbar, P. Dann, G. Robinson, L Hennighausen, J. Zhang, and J. Wysolmerski
Parathyroid hormone-related protein signaling is necessary for sexual dimorphism during embryonic mammary development
Development, January 8, 1999; 126(16): 3485 - 3493.
[Abstract] [PDF]

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 EndocrinologyHome page
B. Lanske, P. Divieti, C. S. Kovacs, A. Pirro, W. J. Landis, S. M. Krane, F. R. Bringhurst, and H. M. Kronenberg
The Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mediates Actions of Both Ligands in Murine Bone
Endocrinology, December 1, 1998; 139(12): 5194 - 5204.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
W. M. Philbrick, B. E. Dreyer, I. A. Nakchbandi, and A. C. Karaplis
Parathyroid hormone-related protein is required for tooth eruption
PNAS, September 29, 1998; 95(20): 11846 - 11851.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
S. E. Porter, R. L. Sorenson, P. Dann, A. Garcia-Ocana, A. F. Stewart, and R. C. Vasavada
Progressive Pancreatic Islet Hyperplasia in the Islet-Targeted, Parathyroid Hormone-Related Protein-Overexpressing Mouse
Endocrinology, September 1, 1998; 139(9): 3743 - 3751.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
H. Plotkin, C. Gundberg, M. Mitnick, and A. F. Stewart
Dissociation of Bone Formation from Resorption during 2-Week Treatment with Human Parathyroid Hormone-Related Peptide-(1-36) in Humans: Potential as an Anabolic Therapy for Osteoporosis
J. Clin. Endocrinol. Metab., August 1, 1998; 83(8): 2786 - 2791.
[Abstract] [Full Text]

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 EndocrinologyHome page
S. Rihani-Bisharat, G. Maor, and D. Lewinson
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, March 1, 1998; 139(3): 974 - 981.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
T. A. Guise and G. R. Mundy
Cancer and Bone
Endocr. Rev., February 1, 1998; 19(1): 18 - 54.
[Abstract] [Full Text]

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 DevelopmentHome page
J. Wysolmerski, W. Philbrick, M. Dunbar, B Lanske, H Kronenberg, and A. Broadus
Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development
Development, January 4, 1998; 125(7): 1285 - 1294.
[Abstract] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
T. Massfelder, P. Dann, T. L. Wu, R. Vasavada, J.-J. Helwig, and A. F. Stewart
Opposing mitogenic and anti-mitogenic actions of parathyroid hormone-related protein in vascular smooth muscle cells: A critical role for nuclear targeting
PNAS, December 9, 1997; 94(25): 13630 - 13635.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
C. S. Kovacs and H. M. Kronenberg
Maternal-Fetal Calcium and Bone Metabolism During Pregnancy, Puerperium, and Lactation
Endocr. Rev., December 1, 1997; 18(6): 832 - 872.
[Abstract] [Full Text]

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 EndocrinologyHome page
L. K. McCauley, A. J. Koh, C. A. Beecher, and T. J. Rosol
Proto-Oncogene c-fos Is Transcriptionally Regulated by Parathyroid Hormone (PTH) and PTH-Related Protein in a Cyclic Adenosine Monophosphate-Dependent Manner in Osteoblastic Cells
Endocrinology, December 1, 1997; 138(12): 5427 - 5433.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
M. Wolzt, L. Schmetterer, G. Dorner, G. Zelger, J. Entlicher, S. Kapiotis, and H.-G. Eichler
Hemodynamic Effects of Parathyroid Hormone-Related Peptide-(1-34) in Humans
J. Clin. Endocrinol. Metab., August 1, 1997; 82(8): 2548 - 2551.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
H. M. Kronenberg
Editorial: Parathyroid Hormone and Osteocalcin--When Friends Become Strangers
Endocrinology, August 1, 1997; 138(8): 3083 - 3084.
[Full Text] [PDF]

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 EndocrinologyHome page
J. L. Funk, A. H. Moser, C. Grunfeld, and K. R. Feingold
Parathyroid Hormone-Related Protein Is Induced in the Adult Liver during Endotoxemia and Stimulates the Hepatic Acute Phase Response
Endocrinology, July 1, 1997; 138(7): 2665 - 2673.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
T. Ono, K. Inokuchi, A. Ogura, Y. Ikawa, Y. Kudo, and S. Kawashima
Activity-dependent Expression of Parathyroid Hormone-related Protein (PTHrP) in Rat Cerebellar Granule Neurons. REQUIREMENT OF PTHrP FOR THE ACTIVITY-DEPENDENT SURVIVAL OF GRANULE NEURONS
J. Biol. Chem., May 30, 1997; 272(22): 14404 - 14411.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. Dittmer, C. A. Pise-Masison, K. E. Clemens, K.-S. Choi, and J. N. Brady
Interaction of Human T-cell Lymphotropic Virus Type I Tax, Ets1, and Sp1 in Transactivation of the PTHrP P2 Promoter
J. Biol. Chem., February 21, 1997; 272(8): 4953 - 4958.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Z. Huang, Y. Chen, S. Pratt, T.-H. Chen, T. Bambino, R. A. Nissenson, and D. M. Shoback
The N-terminal Region of the Third Intracellular Loop of the Parathyroid Hormone (PTH)/PTH-related Peptide Receptor Is Critical for Coupling to cAMP and Inositol Phosphate/Ca2+ Signal Transduction Pathways
J. Biol. Chem., December 27, 1996; 271(52): 33382 - 33389.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
T. L. Wu, R. C. Vasavada, K. Yang, T. Massfelder, M. Ganz, S. K. Abbas, A. D. Care, and A. F. Stewart
Structural and Physiologic Characterization of the Mid-region Secretory Species of Parathyroid Hormone-related Protein
J. Biol. Chem., October 4, 1996; 271(40): 24371 - 24381.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
I. A. Nakchbandi, E. E. Weir, K. L. Insogna, W. M. Philbrick, and A. E. Broadus
Parathyroid hormone-related protein induces spontaneous osteoclast formation via a paracrine cascade
PNAS, June 20, 2000; 97(13): 7296 - 7300.
[Abstract] [Full Text] [PDF]


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