scholarly journals Parathyroid Hormone-Related Protein, Its Regulation of Cartilage and Bone Development, and Role in Treating Bone Diseases

2016 ◽  
Vol 96 (3) ◽  
pp. 831-871 ◽  
Author(s):  
T. John Martin
Keyword(s):  
Parathyroid Hormone ◽  
Bone Remodeling ◽  
Hormonal Regulation ◽  
Placental Transfer ◽  
Physiological Function ◽  
Bone Diseases ◽  
Endochondral Bone Formation ◽  
Related Protein ◽  
Amino Terminal ◽  
Parathyroid Hormone Related Protein

Although parathyroid hormone-related protein (PTHrP) was discovered as a cancer-derived hormone, it has been revealed as an important paracrine/autocrine regulator in many tissues, where its effects are context dependent. Thus its location and action in the vasculature explained decades-long observations that injection of PTH into animals rapidly lowered blood pressure by producing vasodilatation. Its roles have been specified in development and maturity in cartilage and bone as a crucial regulator of endochondral bone formation and bone remodeling, respectively. Although it shares actions with parathyroid hormone (PTH) through the use of their common receptor, PTHR1, PTHrP has other actions mediated by regions within the molecule beyond the amino-terminal sequence that resembles PTH, including the ability to promote placental transfer of calcium from mother to fetus. A striking feature of the physiology of PTHrP is that it possesses structural features that equip it to be transported in and out of the nucleus, and makes use of a specific nuclear import mechanism to do so. Evidence from mouse genetic experiments shows that PTHrP generated locally in bone is essential for normal bone remodeling. Whereas the main physiological function of PTH is the hormonal regulation of calcium metabolism, locally generated PTHrP is the important physiological mediator of bone remodeling postnatally. Thus the use of intermittent injection of PTH as an anabolic therapy for bone appears to be a pharmacological application of the physiological function of PTHrP. There is much current interest in the possibility of developing PTHrP analogs that might enhance the therapeutic anabolic effects.

Circulating levels of immunoreactive parathyroid hormone-related protein and intact parathyroid hormone in human fetuses and newborns

1996 ◽  
Vol 134 (4) ◽  
pp. 437-442 ◽  
Author(s):  
Nicholas E Papantoniou ◽  
Peter D Papapetrou ◽  
Aristidis J Antsaklis ◽  
Panayotis E Kontoleon ◽  
Spyros A Mesogitis ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Reproductive Age ◽  
Fetal Life ◽  
Intact Parathyroid Hormone ◽  
Human Fetuses ◽  
Related Protein ◽  
Amino Terminal ◽  
Parathyroid Hormone Related Protein ◽  
Circulating Levels ◽  
Immunoreactive Parathyroid Hormone

Papantoniou NE, Papapetrou PD, Antsaklis AJ, Kontoleon PE, Mesogitis SA, Aravantinos D. Circulating levels of immunoreactive parathyroid hormone-related protein and intact parathyroid hormone in human fetuses and newborns. Eur J Endocrinol 1996;134:437–42. ISSN 0804–4643 Undetectable or extremely low levels of circulating immunoreactive parathyroid hormone (PTH) have been reported in human newborns while PTH bioactivity was high. This prompted the hypothesis that the fetal calcemic hormone might be PTH-related protein. The purpose of this study was to measure circulating immunoreactive PTH-related protein in human fetuses and newborns in order to investigate this hypothesis. Parathyroid hormone-related protein (PTHrP(1–86)) and intact PTH were measured using two-site immunoradiometric assays in plasma obtained by cordocentesis from 23 fetuses (19–33 weeks of gestation), from 17 newborns at term (38–41 weeks), from their mothers and from 22 normal women of reproductive age. Plasma PTHrP was detectable in all but one of the fetuses and newborns and in all the mothers and the controls. The mean level was similar among fetuses (19–33 weeks) (0.43 ± 0.18 pmol/l), newborns (0.48 ±0.12), mothers (0.48 ±0.14) and normal controls (0.46 ± 0.09). Plasma PTH was found to be significantly higher in fetuses at midgestation (1.0 ± 0.99 pmol/l) than in the newborns (0.22 ± 0.21) (p < 0.0025); maternal PTH was significantly higher compared to fetal level at mid-gestation (2.1 ± 1.0, p < 0.01) as well as at term (2.69 ± 1.40, p < 0.001). In the control women PTH was 3.07 ± 1.25 pmol/l. These results showed that plasma amino-terminal PTHrP-(1–86)) is detectable during the second half of human fetal life and its level remains unchanged during this period of time, in contrast to changing levels of fetal plasma PTH. The relatively low PTHrP-(1–86) level that we found in the newborns is not responsible for the high PTH-like bioactivity found by some investigators in cord blood at term. Peter D Papapetrou, Second Division of Endocrinology, "Alexandra" Hospital, 80 Vas. Sofias & Lourou Streets, Athens 115 28, Greece

Actions of parathyroid hormone-related protein on the rat kidney in vivo

1989 ◽  
Vol 122 (1) ◽  
pp. 229-235 ◽  
Author(s):  
H. Zhou ◽  
D. D. Leaver ◽  
J. M. Moseley ◽  
B. Kemp ◽  
P. R. Ebeling ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Infusion Rate ◽  
Rat Kidney ◽  
Physiological Activity ◽  
Calcium Excretion ◽  
Related Protein ◽  
Renal Handling ◽  
Amino Terminal ◽  
Parathyroid Hormone Related Protein

ABSTRACT Peptides containing residues 1–34 of parathyroid hormone-related protein (PTHrP) and of bovine parathyroid hormone (bPTH), and recombinant full-length PTHrP(1–141) were infused i.v. into anaesthetized thyroparathyroidectomized rats to compare their action and potency on the renal handling of calcium, phosphate and cyclic AMP (cAMP) in vivo. All three peptides decreased the excretion of calcium and increased the excretion of phosphate and cAMP in the urine, with PTHrP(1–34) and PTHrP(1–141) having virtually equipotent effects. Thus the essential requirements for the major physiological activity of PTHrP on the kidney are contained within the 34 amino-terminal amino acids. For all three peptides, the lowest infusion rate that increased phosphate and cAMP excretion was 0·01 nmol/kg per h, whereas the lowest infusion rate that decreased calcium excretion was 0·025 nmol/kg per h for the PTHrP peptides and 0·1 nmol/kg per h for bPTH(1–34). The response to the PTHrP peptides was maximal at an infusion rate of 01 nmol/kg per h for both calcium and phosphate. Since the kidney is either equally sensitive to PTHrP and bPTH(1–34), or more sensitive to PTHrP than to bPTH(1–34), the hypercalcaemia of humoral hypercalcaemia of malignancy may develop because uncontrolled secretion of PTHrP increases the renal reabsorption of calcium to such an extent that even a modest increase in the inflow of calcium into the blood raises plasma calcium concentration. Journal of Endocrinology (1989) 122, 229–235

scholarly journals Coherent Expression Chromosome Cluster Analysis Reveals Differential Regulatory Functions of Amino-Terminal and Distal Parathyroid Hormone-Related Protein Domains in Prostate Carcinoma

2005 ◽  
Vol 2005 (4) ◽  
pp. 353-363 ◽  
Author(s):  
I. Tsigelny ◽  
D. W. Burton ◽  
Y. Sharikov ◽  
R. H. Hastings ◽  
L. J. Deftos
Keyword(s):  
Parathyroid Hormone ◽  
Cancer Cell ◽  
Prostate Carcinoma ◽  
Human Cancer ◽  
Expression Profiles ◽  
Cancer Cell Line ◽  
Biologically Active ◽  
Related Protein ◽  
Amino Terminal ◽  
Parathyroid Hormone Related Protein

Parathyroid hormone-related protein (PTHrP) has a number of cancer-related actions. While best known for causing hypercalcemia of malignancy, it also has effects on cancer cell growth, apoptosis, and angiogenesis. Studying the actions of PTHrP in human cancer is complicated because there are three isoforms and many derived peptides. Several peptides are biologically active at known or presumed cell surface receptors; in addition, the PTHrP-derived molecules can exert effects at the cell nucleus. To address this complexity, we studied gene expression in a DU 145 prostate cancer cell line that was stably transfected with control vector, PTHrP 1-173 and PTHrP 33-173. With this model, regulatory effects of the amino-terminal portion of PTHrP would result only from transduction with the full-length molecule, while effects pertaining to distal sequences would be evident with either construct. Analysis of the expression profiles by microarrays demonstrated nonoverlapping groups of differentially expressed genes. Amino-terminal PTHrP affected groups of genes involved in apoptosis, prostaglandin and sex steroid metabolism, cell-matrix interactions, and cell differentiation, while PTHrP 33-173 caused substantial increases in MHC class I antigen expression. This work demonstrates the distinct biological actions of the amino-terminus compared to distal mid-molecule or carboxy-terminal sequences of PTHrP in prostate carcinoma cells and provides targets for further study of the malignant process.

Overexpression of parathyroid hormone-related protein or parathyroid hormone in transgenic mice impairs branching morphogenesis during mammary gland development

Development ◽  
1995 ◽  
Vol 121 (11) ◽  
pp. 3539-3547 ◽  
Author(s):  
J.J. Wysolmerski ◽  
J.F. McCaughern-Carucci ◽  
A.G. Daifotis ◽  
A.E. Broadus ◽  
W.M. Philbrick
Keyword(s):  
Parathyroid Hormone ◽  
Transgenic Mice ◽  
Branching Morphogenesis ◽  
Mammary Glands ◽  
Myoepithelial Cells ◽  
Breast Development ◽  
Related Protein ◽  
Amino Terminal ◽  
Parathyroid Hormone Related Protein ◽  
Breast Hypoplasia

Parathyroid hormone-related protein (PTHrP) was originally discovered as the tumor product that causes humoral hypercalcemia of malignancy. PTHrP is now known to be widely expressed in many normal fetal tissues where it may participate in the regulation of organogenesis. In this report, we document that overexpression of PTHrP in myoepithelial cells in the mammary glands of transgenic mice resulted in a form of breast hypoplasia characterized by a profound defect in branching morphogenesis of the developing mammary duct system. In addition, transgenic mice manifested a defect in lobuloalveolar development during pregnancy that seemed to be, in part, the consequence of an impaired ability to form terminal ducts in response to estrogen and progesterone stimulation. The effects of PTHrP on branching morphogenesis during breast development appeared to be the result of amino-terminal PTH-like sequences that signal through the PTH/PTHrP receptor, since overexpression of parathyroid hormone itself in the mammary glands of transgenic mice caused a similar development phenotype, and delivery of PTHrP (1–36) via locally implanted slow-release pellets impaired breast development in normal mice. These results suggest that PTHrP, which is a native product of mammary epithelial and myoepithelial cells may participate in normal breast development, perhaps as a locally secreted growth inhibitor.

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