Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parathyroid hormone-like factors have been found in extracts of tumors associated with humoral hypercalcemia of malignancy, many of which are of squamous epithelial origin. Cultured, nonmalignant human keratinocytes were examined for the production of similar factors. Keratinocyte-conditioned medium from ten cultures stimulated the production of cyclic adenosine monophosphate in clonally derived rat osteosarcoma cells sensitive to parathyroid hormone. Bovine [Nle8,18, Tyr34]PTH-(3-34)NH2, a competitive inhibitor of parathyroid hormone, stopped the adenylate cyclase production stimulated by keratinocyte-conditioned medium, but antisera to parathyroid hormone had no effect on such adenylate cyclase activity. The active component of keratinocyte-conditioned medium has a molecular weight exceeding that of native parathyroid hormone. These characteristics are shared by the parathyroid hormone receptor agonists associated with humoral hypercalcemia of malignancy, which suggests that normal human keratinocytes may produce a factor related to that produced by malignant tumors associated with humoral hypercalcemia of malignancy.
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PMID:A parathyroid hormone-like protein from cultured human keratinocytes. 241 17

The tumor line CAC-8, is a serially transplantable adenocarcinoma maintained in nude mice which originated from a hypercalcemic dog. Nude mice with CAC-8 developed a syndrome of humoral hypercalcemia of malignancy. CAC-8 contained a protein factor which stimulated adenylate cyclase of bone and kidney cells in vitro. The adenylate cyclase (AC) of rat osteosarcoma cell lines, ROS 17/2.8 (ROS) and UMR-106, was stimulated by the tumor extract and potentiated by forskolin (0.1 microM). The ROS cells responded to the lowest concentration of CAC-8 extract, but UMR cells responded with a greater increase in AC activity compared to controls following exposure to CAC-8 extract. Pretreatment of ROS 17/2.8 cells with dexamethasone enhanced the response to CAC-8 extract. The opossum kidney cell line (OK) was less sensitive to the AC-stimulating activity of CAC-8 extract, but AC stimulation was increased in the presence of forskolin. Bovine (1-34) parathyroid hormone (BPTH) (10 nM) stimulated AC equally in ROS, UMR, and OK cells. Isoproterenol (1.0 microM) stimulated AC activity in ROS and UMR cells but not in OK cells. The AC-stimulating activity of CAC-8 appeared to bind to the parathyroid hormone receptor of ROS, UMR, and OK cells since addition of the parathyroid hormone receptor antagonist, [8,18norleucine, 34tyrosine]BPTH (3-34) amide, inhibited CAC-8-mediated cyclic adenosine 5'-monophosphate production and alone did not stimulate AC activity. The AC-stimulating activity of CAC-8 was acid and heat stable. Trypsin digestion reduced BPTH and CAC-8 stimulation of AC to near basal levels and treatment of CAC-8 extract with dithiothreitol reduced AC stimulation in UMR cells by approximately 50%. Extracts of the hypercalcemic tumor line (CAC-8) contained bone and kidney AC-stimulating activity which was enhanced by forskolin and dexamethasone, inhibited by [8,18Nle, 34Tyr]BPTH (3-34) amide, heat stable, trypsin sensitive, inactivated by reduction, and had a relative molecular weight of 34,000 by gel exclusion chromatography. Isolation and characterization of the factor(s) produced by CAC-8 that stimulate AC activity will be useful in further understanding the pathogenesis of humoral hypercalemia of malignancy in animal and human patients.
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PMID:Bone and kidney adenylate cyclase-stimulating activity produced by a hypercalcemic canine adenocarcinoma line (CAC-8) maintained in nude mice. 346 38

UMR-106 rat osteogenic sarcoma cells express two calcium signaling P2 purinergic receptors. One is a P2U receptor with EC50's for adenosine triphosphate (ATP) and uridine triphosphate (UTP) of 2.6 and 2.4 microM, respectively. The other is a novel P2T receptor for adenosine diphosphate (ADP) (EC50 0.4 microM), adenosine 5'-O-(2-thiodiphosphate). (EC50 5 microM), 2-methylthio ATP (EC50 0.2 microM), and 2-methylthio ADP (EC50 0.04 microgram M). Responses to these ligands are desensitized by ADP but not by UTP. Responses to UTP and ATP are desensitized by UTP but not by ADP or adenosine 5'-O-(2-thiodiphosphate). 2-ChloroATP interacts with both receptors at high concentrations but with only the P2T receptor at low concentrations (EC50 0.05 microM). The weak platelet P2T receptor antagonist AMP blocks this P2T and not the P2U receptor. Addition of ATP after UTP desensitization of P2U receptors inhibits subsequent responsiveness to ADP but evidence for rapid conversion of ATP to ADP complicates interpretation of this apparent antagonism of P2T receptors by ATP. A subpassage of UMR-106.P135 cells lose P2U but retain P2T ligand responsiveness. Activation of either P2 receptor increases cellular IP3 concentrations in UMR-106 cells. Neither receptor can activate divalent cation entry as evidenced by their lack of effect on Mn++ quenching of fura-2 fluorescence. Neither receptor can modify parathyroid hormone receptor-mediated elevation of cellular cyclic AMP. This receptor for ADP demonstrates many of the same characteristics of the ADP receptor which we have previously reported as a P2T receptor expressed in K562 and Dami cells.
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PMID:Separate P2T and P2U purinergic receptors with similar second messenger signaling pathways in UMR-106 osteoblasts. 801 49

The effect of transforming growth factor beta1 (TGF-beta1) on the expression of mRNA for the parathyroid hormone receptor and binding of iodinated parathyroid hormone-related protein in ROS 17/2.8 osteosarcoma cells was evaluated. TGF-beta1 stimulated a 2-7-fold increase in steady state mRNA levels for the parathyroid hormone receptor at a maximal dose of 5 ng/ml, with increased levels of expression at 6 h of TGF-beta1-incubation, and peak levels at 8-24 h. Receptor binding studies revealed a significant increase in PTHrP-specific binding with TGF-beta1 doses as low as 0.5 ng/ml and a 55% increase in numbers of receptors with no alteration in binding affinity with 5.0 ng/ml TGF-beta1. Time course studies indicated that receptor binding was increased at 24 h with peak levels reached at 48 h of treatment. PTH-stimulated cAMP levels were significantly increased in ROS 17/2.8 cells treated with TGF-beta1 (0.5 ng/ml) for 48 h. These data indicate that TGF-beta1 upregulates steady-state mRNA, ligand binding and PTH/PTHrP receptor signaling in rat osteosarcoma cells. The effects of TGF-beta1 on bone may be attributed in part to regulation of the PTH/PTHrP receptor at the molecular level.
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PMID:Transforming growth factor-beta1 regulates steady-state PTH/PTHrP receptor mRNA levels and PTHrP binding in ROS 17/2.8 osteosarcoma cells. 939 68

Primitive cells of the osteoblast lineage are not well characterized but are known to be present within the STRO-1+ fraction of adult human bone and marrow. A survey of human osteosarcoma cell lines revealed that STRO-1 is expressed by MG-63 but not SaOS-2. Among murine cell lines tested, expression of STRO-1 was detected in the bipotential (adipocyte/osteoblast) line BMS-2 but not the committed osteoblast precursor MC3T3-E1. A proportion of cultured adult human bone marrow stromal cells (BMSCs) consistently expressed the STRO-1 antigen. The expression of a range of cell surface antigens was studied in relation to STRO-1 by flow cytometry and several, including the bone/liver/kidney isoform of alkaline phosphatase (ALP), were found to subtype the STRO-1+ population of BMSCs. Further, BMSCs dual-labeled with antibodies recognizing STRO-1 and ALP could be assigned to one of four fractions: STRO-1-/ALP-, STRO-1+/ALP-, STRO-1+/ALP+, and STRO-1-/ALP+. Cells from each fraction could be isolated in high purity and, when recultured, remained viable and exhibited a limited degree of phenotypic stability. Using reverse transcriptase-polymerase chain reaction, cells in the four fractions were found to express different levels of transcripts for the parathyroid hormone receptor (PTHr) and bone sialoprotein (BSP). The expression of transcripts for the nuclear transcription factor core-binding factor alpha 1/osteoblast-specific factor-2 (CBFA1/OSF2) was restricted to those fractions expressing STRO-1 and/or ALP. Treatment with 10 nM dexamethasone consistently increased the proportion of cells present in those fractions which expressed the highest levels of transcripts for PTHr and BSP (STRO-1+/ALP+ and STRO-1-/ALP+) while simultaneously decreasing the proportion present in the STRO-1+/ALP- fraction. In conclusion, the expression of STRO-1 in vitro remains a characteristic of less well differentiated cells of the osteoblast lineage; in cultures of BMSCs and in established human osteosarcoma cell lines, there is an inverse association between the expression of STRO-1 and ALP; dual labeling of BMSCs with monoclonal antibodies recognizing STRO-1 and ALP permits the identification and isolation of cells of the osteoblast lineage at different stages of differentiation.
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PMID:Further characterization of cells expressing STRO-1 in cultures of adult human bone marrow stromal cells. 1045 67

Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that HOSM-1 cells, an osteosarcoma cell line established from human mandible, expressed mRNA for osteoblastic markers, such as alkaline phosphatase, osteonectin, osteocalcin and parathyroid hormone receptor, thus exhibiting an osteoblastic phenotype. We have investigated a possible role of cyclic nucleotide phosphodiesterases (PDEs) in osteosarcoma cells. RT-PCR analysis revealed that HOSM-1 cells expressed mRNA for PDE4A, 4B and 4C. In addition, rolipram, a specific inhibitor of PDE4, inhibited HOSM-1 cell proliferation. The finding that PDE4 is involved in proliferation of osteosarcoma cells suggests the possibility that PDE4 may be a new target for antitumor therapy.
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PMID:Phosphodiesterase 4 in osteoblastic osteosarcoma cells as a potential target for growth inhibition. 1278 45

The ideal treatment of osteoporosis should preferably prevent fractures through normalization of bone mass and bone micro-architecture. Biosynthetic human parathyroid hormone 1-34 (teriparatide) was recently approved in the EU and the USA as the first anabolic treatment of osteoporosis. The effects of teriparatide are mediated by the G-protein-dependent, parathyroid hormone receptor-1 in the cell membrane. The binding of the ligand to the receptor activates adenylate cyclase and a number of phospholipases (A, C, and D) and increases intracellular levels of cAMP and calcium. Intermittent teriparatide increases the number of osteoblasts and bone formation by activation of pre-existing osteoblasts, increased differentiation of lining cells, and reduced osteoblast apoptosis. Anabolic effects of teriparatide on bone have been demonstrated in several species. It increases bone mass, structural integrity, bone diameter, and bone strength. Clinical efficacy was demonstrated in a randomized study comprising 1637 post-menopausal women with osteoporosis showing a 65% and 35% reduction of the relative risk of vertebral and appendicular fractures, respectively, during 18 months of treatment. Moreover, bone mineral density in the lumbar spine and hip increased by 9.7% and 2.6%, respectively. Similar effects on bone mineral density have been reported in men with osteoporosis and in glucocorticoid-induced osteoporosis, however, fracture data are limited in these groups. Direct comparison with alendronate revealed that teriparatide has a more pronounced effect on bone mineral density. Teriparatide should be used in combination with calcium plus vitamin D, and may be combined with hormonal replacement therapy. In contrast, alendronate attenuates the effect of teriparatide. The efficacy of other combinations remains uncertain. After termination of teriparatide, bone mineral density of the lumbar spine is reduced by approximately 2-3% after 2 1/2 years. This decrease is prevented by treatment with bisphosphonates. The most frequent adverse effects with teriparatide are nausea, headache, dizziness, and leg cramps, however, only the latter two differed significantly between the groups receiving teriparatide 20 microg/day and placebo. In the pivotal clinical study, reduced dosage or termination of therapy due to hypercalcaemia was necessary in 3% and 0.2%, respectively. In a rat toxicology study, in which teriparatide was administered in high dosages for an extended period of time, osteosarcoma was seen in a significant number of animals. However, none of the approximately 2800 patients in clinical trials has developed osteosarcoma. Teriparatide constitutes a break-through in the treatment of severe osteoporosis, although a number of issues about the optimal use of teriparatide remains unsettled. The published data provide proof of concept on anabolic therapy which changes several paradigms of bone physiology. Other parathyroid hormone analogues are being investigated in clinical trials and the development of non-peptide, small molecules targeted at the parathyroid hormone receptor may be envisaged.
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PMID:Teriparatide (biosynthetic human parathyroid hormone 1-34): a new paradigm in the treatment of osteoporosis. 1522 97

Type 1 parathyroid hormone receptor (PTH1R) activation, desensitization, internalization, and recycling proceed in a cyclical manner. The Na(+)/H(+) exchange regulatory factor 1 (NHERF1) is a cytoplasmic adapter protein that regulates trafficking and signaling of several G protein-coupled receptors (GPCRs) including the PTH1R. The mineral ion wasting and bone phenotype of NHERF1-null mice suggests that PTH1R may interact with NHERF1. The objective of this study was to examine the effect of NHERF1 on PTH1R desensitization. Using rat osteosarcoma T6-N4 cells expressing the endogenous PTH1R, in which NHERF1 expression could be induced by tetracycline, PTH1R desensitization was assessed by measuring adenylyl cyclase activity after successive PTH challenges. PTH1R-mediated adenylyl cyclase responses were desensitized by repetitive PTH challenges in a concentration-dependent manner, and desensitization was inhibited by NHERF1. NHERF1 blocked PTH-induced dissociation of the PTH1R from Galpha(s). Blocking PTH1R endocytosis did not mitigate PTH1R desensitization. Reducing constitutive NHERF1 levels in human osteosarcoma SAOS2 cells, which express both endogenous PTH1R and NHERF1, with short hairpin RNA directed against NHERF1 restored PTH1R desensitization. Mutagenesis of the PDZ-binding domains or deletion of the NHERF1 MERM domain demonstrated that both are required for inhibition of receptor desensitization. A phosphorylation-deficient PTH1R exhibited reduced desensitization and interaction with beta-arrestin2 compared with wild-type PTH1R. NHERF1 inhibited beta-arrestin2 binding to wtPTH1R but had no effect on beta-arrestin2 association with pdPTH1R. Such an effect may protect against PTH resistance or PTH1R down-regulation in cells harboring NHERF1.
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PMID:NHERF1 regulates parathyroid hormone receptor desensitization: interference with beta-arrestin binding. 1918 35