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)-related peptide (PTHrP) was determined to be a factor inducing malignancy-associated hypercalcemia by activating a common receptor (PTH/PTHrP receptor) with PTH. PTHrP gene "knock out" mice showed a form of dyschondroplasia due to reduced proliferation of chondrocytes. In addition, heterogenous populations of variously-differentiated chondrocytes were present in the hypertrophic zone of the mutant epiphyseal plate. Although the homozygotes die within several hours after birth, the adult mice, heterozygous for PTHrP gene deletion, showed a delayed skeletal abnormality at 3 month old, with a reduced amount of PTHrP transcript, therefore, PTHrP appears to modulate cell proliferation and differentiation at both fetal and adult stages. The co-localization of PTHrP and its receptor in osteoblastic cells and chondrocytes suggested a paracrine/autocine mode of action manner of these molecules. Recently, fibroblast growth factor receptor 3 (FGFR3) deficient mice demonstrated skeletal defects including kyphosis, scoliosis, crooked tails and curvature and overgrowth of long bones and vertebrae, which are caused by an increase in proliferation. Therefore, it seems that PTHrP and FGFR3 serve as positive and negative regulators on the chondrocyte proliferation, respectively. In this paper, we review our recent studies on the histological abnormality of long bone seen in PTHrP gene deficient- and FGFR3 gene deficient-mice.
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PMID:The biological action of parathyroid hormone-related peptide (PTHrP) and fibroblast growth factor receptor 3 (FGFR3) on bone and cartilage. 1115 87

The propensity for breast cancer cells to metastasize to bone and to induce osteolysis has long been recognized. Characteristics of both the tumor cells and the bone microenvironment contribute to this phenomenon. The presence of tumor in bone is associated with activation of osteoclasts, resulting in excessive bone resorption and subsequent osteolysis. Breast cancer cells and other tumor types influence osteoclastic bone resorption by increasing the number of osteoclasts and enhancing their resorptive activity. Parathyroid hormone-related peptide, in addition to its role in humorally mediated hypercalcemia, is secreted by metastatic breast cancer cells in bone in which it acts as a paracrine factor to stimulate osteoclasts. As bone matrix is broken down by activated osteoclasts, a rich supply of mitogenic factors is released, including insulin-like growth factors, bone morphogenetic proteins, and fibroblast growth factors. Transforming growth factor (TGF)-beta, one of the most abundant of the bone-derived factors, promotes increased production of parathyroid hormone-related peptide by tumor cells, establishing a "vicious cycle" leading to progressive tumor growth and bone destruction. Bisphosphonates interrupt this cycle by inhibiting osteoclasts, in part by inducing osteoclast apoptosis. In several animal models of breast cancer metastasis to bone, bisphosphonates decrease the number of new bone metastases and inhibit progression of existing lesions. A single 3 microg intravenous injection of zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ), a new highly potent bisphosphonate, prevented destruction of trabecular bone in an orthotopic mouse mammary tumor model. Tumor volume in bone was decreased by zoledronic acid in a dose-dependent manner in the same model, and tumor cell apoptosis was increased by zoledronic acid in bone metastases in the 4T1 murine model of mammary carcinoma metastasis. Zoledronic acid at a dose of 1.0 microg/d for 10 days also reduced bone lesion area in a nude mouse model with existing bone metastases. Although bisphosphonates, including zoledronic acid, are able to induce apoptosis in tumor cells in vitro, studies in animal models to date have generally not shown a reduction in nonosseous tumor. Therefore, bisphosphonate-associated tumor reduction in bone is most likely mediated by osteoclast inhibition or is related to high local concentrations of bisphosphonates in the bone compartment.
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PMID:Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. 1134 63

Parathyroid hormone-related peptide (PTHrP) was discovered as the main mediator of humoral hypercalcemia associated with malignancy but is now known to be expressed by a variety of normal fetal and adult tissues. The amino-terminal region of PTHrP reveals limited but significant homology with parathyroid hormone (PTH), resulting in the interaction of either peptide with a common seven-transmembrane spanning G-protein linked receptor termed the PTH/PTHrP receptor. Targeted inactivation of PTHrP and its receptor in mice has established a critical role for this signaling pathway in chondrocyte biology and endochondral bone formation. Animals homozygous for the targeted alleles demonstrate marked skeletal deformities arising from impaired chondrocyte proliferation, premature differentiation and accelerated apoptosis. The complex processes resulting in normal endochondral bone development involve additional factors such as the hedgehog signaling pathway with which PTHrP interacts. PTHrP, like PTH, also binds to receptors on cells of the osteoblast lineage resulting in enhanced bone formation and also, indirectly, augmented osteoclastic bone resorption. The marked premature osteoporosis observed in mice heterozygous for the disrupted Pthrp allele also points to a crucial role for the protein in the maintenance of the adult skeleton. Further studies into this process are likely to reveal new facets of the pathogenesis underlying a variety of metabolic bone diseases and potentially point to new directions for therapeutic interventions.
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PMID:PTHrP: novel roles in skeletal biology. 1137 74

Background: Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTH-rP) are two potent hypercalcemic hormones that act on the same targets. Autonomous secretion of the former is involved in primary hyperparathyroidism (PHPT), whereas the latter is responsible for humoral hypercalcemia of malignancy (HHM). Methods: From 250 consecutive, hypercalcemic serum samples sent to our laboratory for assessment of intact PTH, we were able to obtain clinical information, as well as an additional plasma sample for PTH-rP measurement, in 134 patients. At the time of sampling, patients could be classified into seven groups: cancer without known bone metastases (CaNoMeta, n=36), cancer with bone metastases (CaMeta, n=9), no evidence of cancer (noEvCa, n=71), sarcoidosis (Sarc, n=3), end-stage renal disease (ESRD, n=12), vitamin D overdose (VIT-D, n=2), and hyperthyroidism (Thyr, n=1). Results: In the CaNoMeta group, 29/36 patients had elevated PTH-rP levels, 9/36 patients had inappropriately elevated PTH levels, and 5/36 had elevated levels of both hormones. In the CaMeta group, three of the nine patients had inappropriately elevated PTH levels, two of them with concomitantly elevated PTH-rP levels. In the NoEvCa group, 63/71 patients had an inappropriate elevation of PTH levels and were diagnosed as having PHPT. Four of the 71 patients had elevated levels of both PTH and PTH-rP; three of them were in poor health and died within a short period of time. All of the ESRD patients had very high PTH and normal PTH-rP levels, except for one woman with high PTH-rP and undetectable PTH levels; she died from what later turned out to be a recurrent bladder carcinoma. In the Sarc, Vit-D, and Thyr groups, both PTH and PTH-rP levels were normal. Conclusions: (1) Elevated PTH-rP levels are a common finding in cancer patients without bone metastases. Intact PTH, however, should always be measured in hypercalcemic patients with malignancy because concurrent primary hyperparathyroidism is not rare. (2) Primary hyperparathyroidism accounts for hypercalcemia in 90% of patients without evidence of cancer whose PTH-rP levels may also be found to be elevated in a few cases, even some with surgically demonstrated parathyroid adenoma.
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PMID:Diagnostic approach to hypercalcemia: relevance of parathyroid hormone and parathyroid hormone-related protein measurements. 1139 97

Parathyroid hormone (PTH) increases serum calcium (Ca) by enhancing bone resorption and renal Ca reabsorption. However, detailed mechanisms of enhanced bone resorption by PTH remain to be elucidated. Although PTH has been shown to increase the expression level of osteoblastic matrix metalloproteinase (MMP)-13 in vitro, only limited results are available regarding the in vivo regulation of MMP expression. In the present study, we have examined expression levels of MMPs in PTH-infused rats. Infusion of 1.5 or 2.0 nmol/kg/day rat PTH(1-34) for 3 days resulted in a dose-dependent increase in serum Ca. PTH infusion also decreased serum phosphate levels and increased urinary excretion of Ca and phosphate. Infusion of PTH for 7 days resulted in less severe hypercalcemia and hypophosphatemia. Urinary Ca and phosphate excretion in rats infused for 7 days was less than that in rats infused for 3 days. Northern blot analysis showed that PTH infusion increased the expression level of MMP-13 in calvaria, although it did not affect MMP-2 expression. Furthermore, the time-course and severity of hypercalcemia and hypercalciuria correlated with the expression level of MMP-13. In situ hybridization also showed that PTH infusion increased the expression level of MMP-13 in femora. These results indicate that PTH enhances MMP-13 expression in vivo and suggest that PTH stimulates bone resorption at least partly by enhancing MMP-13 expression.
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PMID:Parathyroid hormone increases the expression level of matrix metalloproteinase-13 in vivo. 1144 12

Humoral hypercalcemia of malignancy (HHM) is a paraneoplastic syndrome rarely associated with pancreatic adenocarcinoma. Parathyroid hormone-related peptide (PTHrP) is the central mediator of this condition. In our patient, hypercalcemia associated with elevated PTHrP was the initial manifestation of metastatic pancreatic adenocarcinoma. Successful palliation of HHM with bisphosphonates and loop diuretics has been previously reported and was effective in our patient. We report the first case of pancreatic adenocarcinoma metastasis after successful resection to present with hypercalcemia.
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PMID:Hypercalcemia mediated by parathyroid hormone-related protein as an early manifestation of pancreatic adenocarcinoma metastasis: a case report. 1147 77

Tumour-induced hypercalcaemia (TIH) is a frequent complication of advanced cancer but has been rarely reported in patients with malignant melanoma, and its pathogenesis remains unexplored. We studied eight patients with TIH and melanoma. We determined the incidence and pathogenesis of this complication and the effects of bisphosphonate therapy. The incidence of TIH in 751 patients with melanoma was 1.1%. All patients had liver and bone metastases at the time of hypercalcaemia. All patients had osteolytic lesions, most often multiple. The median survival was 30 days (range 4-136 days). After rehydration, the mean (+/- SEM) corrected calcium was 3.42 +/- 0.17 mmol/l. Parathyroid hormone levels were adequately suppressed and vitamin D concentrations were normal. Serum osteocalcin, a marker of bone formation, was low, except in the two patients with renal insufficiency, whereas fasting urinary calcium and hydroxyproline were increased, indicating inhibition of bone formation and stimulation of bone resorption. Increased parathyroid hormone-related protein secretion was noted in only one patient. Three of four patients became normocalcaemic after bisphosphonate therapy for a median duration of 2 weeks. In conclusion, hypercalcaemia is a rare complication of melanoma. It occurs in the context of far advanced disease and is essentially due to aggressive lytic bone metastases with an uncoupling in bone turnover. Bisphosphonates can offer short-term palliation.
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PMID:Hypercalcaemia of melanoma: incidence, pathogenesis and therapy with bisphosphonates. 1159 84

Parathyroid hormone increases due to hypocalcemia even in the early phases of renal insufficiency. At the same time, hyperphosphatemia develops due to decreasing renal excretion which, in turn, intensifies secondary hyperparathyroidism. The cornerstones for prevention and therapy of renal osteopathy are, therefore, efficient lowering of phosphate levels and the early substitution of vitamin-D3 metabolites. In a post marketing surveillance (PMS) of almost 2,000 dialysis patients with renal osteopathy, the course of therapy with Alfacalcidol (Bondiol) was observed over a 6-month period. In 55.9% of cases, Alfacalcidol was administered at a daily dose of 0.25 microg. In 26.6% of patients, Alfacalcidol was administered every second day at a dose of 0.25-1 microg/d. In 16.1% of patients, Alfacalcidol was administered as pulse-therapy, mostly at a dose of 1-2 microg once or twice per week. To lower phosphate levels, 54.8% of patients received calcium compounds, 9.2% aluminium compounds, and 21.7% aluminium compounds in combination with calcium compounds. 14.3% of patients did not receive phosphate binding agents. Two thirds of patients had received active vitamin-D3-metabolites prior to commencing therapy with alfacalcidol, most frequently calcitrol. In 58.1%, the dialysis solution used had a calcium concentration of 1.5 mmol/l (44.8%) or lower; whereas in 41.9%, a higher calcium concentration was used--mostly 1.75 mmol/l (3 8%). During the observation period, serum concentrations of calcium and phosphate remained constant, suggesting that the risk of hypercalcemia due to therapy with Alfacalcidol was not increased. It was found that elevated alkaline phosphatase and parathyroid hormone levels could be significantly lowered (statistically). These effects could be observed both in patients who had been previously treated with vitamin-D3-metabolites and in patients without prior therapy. Efficacy and tolerability of therapy with Alfacalcidol was assessed to be very high by the attending nephrologists.
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PMID:Alfacalcidol in the therapy of renal bone disease. 1177 Aug 36

Parathyroid hormone-related peptide (PTHrP) is a mediator of local osteolysis due to breast cancer. Three isoforms of PTHrP, (1-139), (1-141), and (1-173), are products of alternative splicing in humans, but the specific contribution of each of these isoforms to osteolytic metastasis caused by breast cancer has not been evaluated. To determine the role of PTHrP isoforms in breast cancer metastasis to bone, the human breast cancer cell line MDA-MB-231 (MDA-231) was stably transfected with cDNAs for human prepro PTHrP-(1-139), -(1-141), or -(1-173). Stable MDA/PTHrP-(1-139) clones expressed more PTHrP mRNA and secreted more PTHrP protein, compared with MDA/PTHrP-(1-141), -(1-173), or parental MDA-231. Parental MDA-231 cells and clones expressing each isoform had similar growth rates in vitro. In a mouse model of bone metastases, the osteolytic lesion area of radiographs was greatest in mice bearing MDA/PTHrP-(1-139) compared with those bearing MDA/PTHrP-(1-141), -(1-173), or parental MDA-231. Ca(++) and plasma PTHrP concentrations were significantly higher in the MDA/PTHrP-(1-139) compared with the MDA/PTHrP-(1-141), -(1-173), or parental MDA-231 groups. These data demonstrate that the PTHrP-(1-139) isoform was produced to a greater extent than PTHrP-(1-141) or -(1-173), and in vivo enhanced osteolysis with increased plasma PTHrP concentrations and hypercalcemia compared with overexpression of PTHrP-(1-141) or -(1-173).
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PMID:Parathyroid hormone-related protein (PTHrP)-(1-139) isoform is efficiently secreted in vitro and enhances breast cancer metastasis to bone in vivo. 1199 3

Although hypercalcemia has long been recognized as a complication of sarcoidosis, the incidence of hypercalcemia (> or = 11 mg/dl) in Japan is probably less than 5%. 1 alpha, 25(OH)2D3 is the main cause for hypercalcemia in sarcoidosis and overproduced by sarcoid granulomata. Gamma-interferon produced by activated lymphocytes and macrophages plays a major role in the synthesis of 1 alpha, 25(OH)2D3. PTH release is down regulated by high serum concentration of 1 alpha, 25(OH)2D3. Parathyroid hormone related protein may also contribute to the hypercalcemia of sarcoidosis. Treatment of hypercalcemia and hypercalciuria consists of a low calcium diet, adequate hydration, minimization of exposure to sunlight and reducing overproduction of 1 alpha, 25(OH)2D3. Prednisone, 15 to 25 mg/day, is the drug of choice to reduce the overproduction of 1 alpha, 25(OH)2D3.
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PMID:[Hypercalcemia in sarcoidosis]. 1223 75


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