Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parathyroid hormone (PTH) and PTH-related peptide (PTH-rP) bind to a common receptor and initiate second-messenger cascades that stimulate bone turnover and hypercalcemia. However, PTH is more potent than PTH-rP in inducing bone resorption and coupled bone metabolism in intact tissue, suggesting that these proteins elicit dissimilar postreceptor responses. We compared the effects of PTH and PTH-rP on osteoblastic retraction, an early event that must occur before the osteoclast can achieve access to the underlying bone mineral and begin resorption. MC3T3-E1 mouse osteoblasts were incubated in vehicle or 4.8 nM PTH or PTH-rP with or without 1 mM dibutyryl cAMP (Bt2cAMP). Morphologic changes were observed from 0 to 120 min. PTH caused marked retraction within minutes, which was not enhanced by Bt2cAMP. PTH-rP or Bt2cAMP induced slower, more modest retraction than PTH. The combined effect of PTH-rP plus Bt2cAMP was greater than that of PTH-rP, but less than that of PTH. PTH-rP and PTH had similar effects on cAMP generation. Thus, compared to PTH, PTH-rP induces less osteoblastic retractile response, exposing less bone surface to osteoclastic resorption. This may account for its lower hypercalcemic potency in vivo and contribute to its relative inability to stimulate coupled bone resorption and formation.
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PMID:PTH and PTH-rP elicit dissimilar retractile responses in murine MC3T3-E1 osteoblasts. 798 66

Parathyroid hormone related protein (PTHrP) is an important humoral factor in hypercalcaemia of malignancy. In addition there is increasing evidence that this peptide has a physiological role in fetal development, especially in cellular growth and differentiation. Both in-situ hybridization and immunohistochemistry were used together and for the first time to identify sites of PTHrP gene expression and peptide in fetal and extra-embryonic tissues of first trimester human pregnancy. PTHrP mRNA and peptide were identified in the avascular amnion and the syncytiotrophoblast while mRNA alone was expressed in the cytotrophoblast. Its expression in these extra-embryonic tissues is consistent with postulated roles for PTHrP in implantation, relaxation of endometrial muscle and regulation of vascular tone. Expression of both mRNA and peptide occurred in endo-, meso- and ectodermal structures of the fetus, consistent with local production of the peptide rather than cellular uptake from amniotic fluid and supporting a role for PTHrP in cellular growth and differentiation.
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PMID:Parathyroid hormone related protein (PTHrP) gene expression in fetal and extra-embryonic tissues of early pregnancy. 819 40

A 12 year old boy presenting with hypercalcaemia (calcium 3.25 mmol/l) and osteopaenia with multiple osteolytic lesions was found to have acute lymphoblastic leukaemia without lymph-adenopathy or organomegaly. Hypercalcaemia is a rare feature of acute leukaemia, but the patients previously described all show very similar characteristics, which were highlighted in this patient. These include age (10-20 years), severe osteolytic bone lesions, lymphoblastic leukaemia, and normal white cell count with absent or rare circulating blasts. Parathyroid hormone levels were normal in this patient, and response to induction therapy was good. This case demonstrates that acute lymphoblastic leukaemia may present in an atypical form without peripheral blasts but with hypercalcaemia and gross skeletal changes.
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PMID:Hypercalcaemia and multiple osteolytic lesions in childhood acute lymphoblastic leukaemia. 820 50

Parathyroid hormone related peptide (PTHrP) and 1,25-dihydroxyvitamin D are known to be resorptive agents which could contribute to the development of hypercalcemia in humoral hypercalcemia of malignancy (HHM) syndrome in Walker 256 tumor bearing rats. In order to clarify some aspects about the relative contribution of these factors to bone resorption, we have determined the effects produced by PTHrP (1-34) and/or 1,25(OH)2D3 on tartrate resistant acid phosphatase (TRAP), a biochemical marker of bone resorption, in fetal rat calvaria cultures. At the same time, bovine parathyroid hormone (PTH) (1-34) was used as a control in the experiments in order to compare its effects with those produced by the other two agonists. In the present work, 10(-7) M PTH (1-34), 10(-7) M PTHrP (1-34) and 10(-8) M or 10(-10) M 1,25(OH)2D3 produced a significant increase in TRAP activity, when these agonists were added to the calvaria culture. Surprisingly, and in spite of the different ways of action of PTH, PTHrP and 1,25(OH)2D3, their actions are not additive in our experiment. The results of the present work suggest that any of the two implicated factors PTHrP or 1,25(OH)2D3 could be individually responsible for the high rate of bone resorption that takes place in HHM syndrome in Walker 256 carcinosarcoma bearing rats, although other different agents, like TGF, could also be implicated.
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PMID:Parathyroid hormone related peptide (1-34) and 1,25-dihydroxyvitamin D, have no additive effects on bone tartrate resistant acid phosphatase activity in fetal rat calvaria cultures. 822 85

Parathyroid hormone-related peptide (PTHRP) was discovered through its ability to cause parathyroid hormone (PTH)-like effects in malignancy-associated hypercalcemia (MAH). It shares limited amino-terminal sequence homology with PTH and can thus interact with PTH receptors. It was originally isolated, cloned, and sequenced from tumors of patients with MAH. The human PTHRP gene is complex and can generate 3 peptide isoforms of 139, 141, and 173 amino acids. The gene encoding PTHRP in other species is somewhat simpler and generally results in only a single isoform; however, there is marked interspecies amino acid sequence homology in the protein product up to residue 111. PTH and PTHRP genes have similar structural organizations and it is believed that these 2 genes have a common ancestral origin and may have arisen through an ancient gene duplication. There are now several region specific radioimmunoassays, as well as immunoradiometric assays, which have been developed and which have all demonstrated elevated circulating levels of PTHRP in patients with MAH. PTHRP is expressed in a wide variety of tissues and, in addition to its classical PTH-like activities, it may have a local or systemic role in calcium regulation in the fetus and perhaps in the neonate. It may also act locally as a smooth muscle relaxant and a vasorelaxant. Its local role in some fetal tissues and in keratinocytes may take the form of a regulator of cell growth and/or differentiation. Thus when antisense RNA technology was used to inhibit endogenous PTHRP production in an established human keratinocyte cell line, PTHRP was found to inhibit growth and enhance differentiation. Irrespective of its precise normal role however, PTHRP provides a potential therapeutic target in MAH and, with improved methods of detection, may also be useful as a tumor marker.
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PMID:Parathyroid hormone-related peptide. 826 93

Parathyroid hormone related protein (PTHRP) has been implicated in humoral hypercalcaemia of malignancy (HHM). We describe a patient with a renal carcinoma and hypercalcaemia, and for the first time have demonstrated a 4-fold PTHRP concentration gradient across a renal tumour bed. This provides further strong evidence that the primary tumour was the source of the PTHRP. The PTHRP 1-86 content of the tumour tissue was 4.8 ng/g, similar to that previously found in tumours associated with HHM. In PTHRP-secreting tumours, PTHRP may be a useful oncological marker after surgical resection.
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PMID:Humoral hypercalcaemia in renal carcinoma due to parathyroid hormone related protein. 830 45

Parathyroid hormone-like protein (PLP) is expressed in a wide variety of cancers and exerts diverse biological effects in addition to hypercalcemia. We studied the expression of the gene for PLP in cancer cell lines derived from different tissues that produce PLP. We used the polymerase chain reaction to evaluate the PLP mRNA species produced in these various cell lines by differential transcription initiation and alternative splicing pathways. A series of exon-specific oligonucleotide primers that hybridize to DNA sequences adjacent to exon-intron splice junctions throughout the PLP gene were designed. These primers were used to evaluate steady state levels of PLP mRNA species. Our analysis with promoter-specific primers demonstrated expression from all three putative transcription start sites of PLP, designated P1, P2, and P3. P2-initiated transcripts were present in all of the cell lines, whereas the presence of P1- and P3-initiated messages were cell line specific. Our analysis with carboxy-terminal coding-specific primers demonstrated the utilization of the alternative splicing pathways that produce all three mature PLP polypeptides, PLP-139, -1-173, and -1-141. The 1-139 mRNA species was found in all of the cell lines, whereas the 1-141 and 1-173 mRNA species were cell line specific. These studies demonstrate the prevalence of the P2-initiated mRNA and the PLP1-139 alternative splicing pathway in the tumor cell lines studied and suggest that other pathways of PLP gene expression may be regulated in a cell line-dependent manner. The particular form of PLP expressed by a given cell can influence its biological effects.
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PMID:Parathyroid hormone-like protein: alternative messenger RNA splicing pathways in human cancer cell lines. 830 49

Parathyroid hormone-related peptide (PTHrP) is a major factor in the pathophysiology of hypercalcaemia of malignancy. Recent evidence suggests that PTHrP may play an important role in the growth and differentiation of neoplastic as well as non-neoplastic cells. PTHrP was originally detected in normal fetal, but not adult, liver. We have used immunocytochemistry to show that reactive human bile ductules expressing a neuroendocrine phenotype contain immunoreactive PTHrP. These observations raised the possibility that PTHrP immunoreactivity may be useful in the differential diagnosis of primary liver tumours and metastases of adenocarcinoma. A total of 24 primary liver tumours and 22 metastases of adenocarcinoma were studied. All cholangiocarcinomas showed immunopositivity for PTHrP and chromogranin A, while all hepatocellular carcinomas were negative for PTHrP and showed only focal and weak positivity for chromogranin A. Mixed types of primary liver tumour contained PTHrP immunoreactivity only in the areas of cholangiocellular differentiation. Moreover, all metastatic adenocarcinomas were negative for PTHrP and chromogranin A except for two out of five metastatic breast adenocarcinomas. These two patients had bone metastases and hypercalcaemia and thus did not yield differential diagnostic problems with cholangiocarcinoma. None of the patients with cholangiocarcinoma and hepatocellular carcinoma had hypercalcaemia. We conclude that PTHrP is a useful marker for primary cholangiocarcinoma, especially in the differential diagnosis of hepatocellular carcinoma and metastatic adenocarcinoma.
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PMID:Parathyroid hormone-related peptide expression in primary and metastatic liver tumours. 831 35

Parathyroid hormone-related peptide (PTHrP) was originally isolated from tumors associated with the development of hypercalcemia in vivo. Analyses of PTHrP gene expression have demonstrated that PTHrP is also produced in a wide variety of normal fetal and adult nonneoplastic tissues. The results of recent experiments have demonstrated that PTHrP is a growth factor-regulated gene, and different molecular forms of synthetic PTHrP display variable activities in assays for growth factor-like properties in vitro. We have studied the growth factor-like activity of PTHrP in cells transfected with a human PTHrP (hPTHrP) expression vector. Transfected cell lines contained increased amounts of PTHrP mRNA transcripts as assessed by Northern blot analysis. The PTHrP mRNA transcripts were translated into immunoreactive hPTHrP as measured by radioimmunoassay, and conditioned medium from transfected cell lines stimulated cyclic AMP (cAMP) formation in ROS 17/2.8 osteosarcoma cells. The transforming growth factor-beta-like properties of hPTHrP-producing NRK 49F clones were examined using the large-colony transformation assay in soft agar. PTHrP-producing NRK 49F clones did not form large colonies in the presence of epidermal growth factor. In contrast, PTHrP-producing and wild-type NRK 49F cells formed large colonies in the presence of epidermal growth factor and transforming growth factor-beta. No effect on cell growth was observed in PTHrP-producing NRK 49F rat kidney fibroblasts or mouse NIH 3T3 fibroblasts. In contrast, RCB 2.2 osteoblast cells expressing the hPTHrP cDNA were growth inhibited. Incubation of wild-type RCB 2.2 cells with synthetic hPTHrP[1-34] (at concentrations of 1.0-10.0 nM) also produced growth inhibition. PTHrP increased cAMP formation in RCB 2.2 cells but not in NIH 3T3 or NRK 49F cells. Incubation of RCB 2.2 cells with dibutyryl cAMP was also associated with inhibition of cell growth. The results of these studies demonstrate that PTHrP may function as an autocrine growth inhibitor of specific cell types, possibly through a cAMP-dependent pathway.
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PMID:Growth factor-like properties of parathyroid hormone-related peptide in transfected rodent cell line. 831 5

Parathyroid hormone-like protein (PLP) was originally identified from tumors associated with hypercalcemia. Recently, it has been found to be expressed in a stretch-responsive manner in several types of smooth muscle. We studied adult rat heart muscle for the presence of the PLP. Using immunohistology and the PCR, we demonstrated the presence of PLP and its mRNA in all heart chambers. Immunoelectron microscopy demonstrated PLP in secretory vesicles of atrial mycocytes. Using immunoassay, we demonstrated that atria contained a higher concentration of PLP than ventricles. Furthermore, primary cultures of both chambers released PLP into conditioned medium, with atria secreting more than ventricles. Considered with studies of the role of PLP in other tissues, our observations suggest that the production and secretion of PLP by cardiac myocytes represents a calcium-related regulatory function for this stretch-responsive polypeptide in the cardiovascular system. PLP in the heart may be the calcium counterpart for the atrial natriuretic-sodium regulatory axis of the cardiovascular system.
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PMID:Parathyroid hormone-like protein is a secretory product of atrial myocytes. 834 12


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