Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

PTH treatment of UMR 106-01 rat osteosarcoma cells increased 20- to 100-fold medium levels of a discrete insulin-like growth factor binding protein (IGFBP) with M(r) of 29K. Northern analysis of UMR cellular RNA hybridized with a specific IGFBP-5 complementary DNA probe indicated a 6.0-kilobase transcript induced within 2 h in PTH-treated cells. IGFBP-5 messenger RNA (mRNA) abundance was maximal around 6 h and remained elevated after 24 h of treatment. Another rat osteosarcoma cell line (ROS 17/2.8) did not express IGFBP-5 mRNA and did not secrete 29K IGFBP. Induction of IGFBP-5 mRNA by PTH was blocked when RNA synthesis in UMR cells was inhibited by actinomycin D (Bu)2cAMP mimicked the effect of PTH on IGFBP-5 mRNA expression and protein secretion. In addition, a monoclonal antibody against IGF-I (Sm 1.2) inhibited the PTH-induced increase in medium IGFBP-5 without influencing IGFBP-5 transcript levels. Direct addition of IGF-I to UMR cell cultures increased medium IGFBP-5 levels approximately 14-fold, with a modest effect on IGFBP-5 mRNA levels. Studies comparing IGF-I, IGF-II, different IGF-I analogs, and insulin indicated that the predominant IGF effect on IGFBP-5 accumulation was type I IGF receptor independent. Thus, in UMR 106-01 cells, PTH and IGF-I increase extracellular concentrations of IGFBP-5 via distinct but coordinate mechanisms; PTH acts primarily to induce IGFBP-5 mRNA expression through a cAMP-mediated mechanism, and IGF-I appears to interact directly with IGFBP-5 protein to promote its accumulation.
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PMID:Regulation of insulin-like growth factor binding protein-5 messenger ribonucleic acid expression and protein availability in rat osteoblast-like cells. 768 79

Aluminum ion at micromolar concentrations significantly stimulated the [3H]thymidine incorporation into human TE85 osteosarcoma cell DNA. Cells treated with mitogenic concentrations of aluminum ion for 48 h showed biphasic stimulation in secretion of IGFs (insulin-like growth factors) into the conditioned medium. Treatment of the human osteosarcoma TE85 cells with mitogenic doses of aluminum ion for 24 h also markedly and reproducibly increased the steady-state level of IGF-II mRNA in a dose-dependent, biphasic manner. The effect of aluminum ion on the steady-state level of IGF-I mRNA could not be determined since the IGF-I mRNA in these cells was not detectable with our oligodeoxynucleotide probes. To test whether the mitogenic effects of aluminum ion could be mediated through IGFs, the stimulation of [3H]thymidine incorporation of TE85 cells was evaluated in the presence and the absence of an inhibitory IGF binding protein (i.e., IGFBP-4). The presence of IGFBP-4 significantly reduced the stimulation in thymidine incorporation by a mitogenic concentration of aluminum ion. Western ligand blot analysis revealed that mitogenic concentrations of aluminum ion also inhibited the secretion of IGF-binding proteins, particularly the inhibitory IGFBP-4, which could lead to the potentiation of the overall activity of IGFs. In conclusion, these findings are consistent with the premise that the mitogenic action of aluminum ion on human bone cells is, in part, mediated by an increased local bone cell production and activity of IGFs.
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PMID:Mechanism of mitogenic action of aluminum ion on human bone cells: potential involvement of the insulin-like growth factor regulatory system. 768 79

The transplantation of PA-III rat prostate cancer cells onto rat skeleton produces osteoblastic metastases. Therefore w e studied the paracrine interactions between the PA-III cells and osteoblast-derived osteosarcoma cells (UMR 106 cells). A serine protease secreted by PA-III cells hydrolyzed IGF-binding protein-1 and IGF-binding protein-2 (IGFBP-1 and IGFBP-2) detected in the cell culture media (CM) of OMR 106 cells by western ligand blotting. The serine protease of PA-III cell CM was purified using a benzamidine affinity column. This protease was a protein of 45-50 kDa on polyacrylamide gel electrophoresis under non-reducing conditions but generated two protein bands under reducing conditions; a) one of 33-35 kDa possessing protease activity and b) another of 20-25 kDa which was proteinolytically inactive. Sequence analysis identified the amino acid sequence of the a-chain (20-25 kDa band) and of the b-chain (33-35 kDa band) of rat urokinase-type plasminogen activator molecule. Urokinase purified from PA-III cell CM hydrolyzed IGFBPs of UMR 106 cells and stimulated the proliferation of UMR 106 cells in serum-free cultures. Its protease activity was abolished by benzamidine and aprotinin. Its mitogenic activity for osteoblasts was inhibited by anti-IGF-I monoclonal antibody. Northern blot analysis documented the expression of the urokinase-type plasminogen activator gene in the mRNA extracted from PA-III cells. Urokinase expression was inhibited by dexamethasone. Therefore, we conclude that urokinase-type plasminogen activator stimulates osteoblasts via an IGF-I dependent mechanism. Hydrolysis of the IGFBOPs at the sites of PA-III cell-induced bone tumors account for an increased bioavailability of IGFs. This may facilitate the development and the growth of PA-III cell-induced bone tumor and can also mediate the subsequent local osteoblastic reaction.
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PMID:Urokinase-type plasminogen activator: a paracrine factor regulating the bioavailability of IGFs in PA-III cell-induced osteoblastic metastases. 768 89

In vitro exposure to low-energy, combined magnetic fields (CMF) increased the release of insulin-like growth factor (IGF)-II from human TE-85 osteosarcoma cells. Short-term CMF exposure of only 10 min increased IGF-II levels in conditioned medium 1 h post CMF exposure. IGF-II levels were measured with a radioreceptor assay using H-35 cells that contain abundant IGF-II but not IGF-I receptors. This assay also uses a recently validated BioGel P-10 acid gel filtration method to remove IGF binding protein before quantitation of either IGF-I or IGF-II. In addition to an increase in IGF-II levels, DNA synthesis, as an index of cell proliferation, was increased during the 24-h period post CMF exposure. A monoclonal antibody against IGF-II blocked the increase in cell proliferation following CMF exposure, whereas a control monoclonal antibody against osteocalcin did not attenuate the mitogenic action of CMF exposure. The effect of CMF exposure to increase both cell proliferation and IGF-II was cell-density dependent with greater stimulation by CMF observed at lower densities. Together, these data are consistent with the hypothesis that CMF exposure stimulates release/production of IGF-II from bone cells and that increased IGF-II then promotes an increase in cell proliferation.
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PMID:Combined magnetic fields increase insulin-like growth factor-II in TE-85 human osteosarcoma bone cell cultures. 778 37

Vascular endothelial growth factor (VEGF), a secreted endothelial cell-specific mitogen, is produced in endocrine organs and regulated by trophic hormones. Because angiogenesis and osteogenesis are closely regulated, we studied whether human osteoblast-like cells produce VEGF, and if so, what factors regulate VEGF mRNA expression. Human osteoblast-like cells (HObLC) derived from trabecular bone explants were cultured in alpha-MEM supplemented with 10% fetal calf serum. Northern blot analysis revealed that HObLC expressed VEGF mRNA, as did several human osteosarcoma cells. 1,25-(OH)2D3 increased the steady-state levels of VEGF mRNA in a time- and concentration-dependent manner in HObLC and one of the osteosarcoma cell lines, SaOS-2, accompanied by an increase in the concentration of immunoreactive VEGF in the conditioned medium. PTH and IGF-I also increased the level of VEGF mRNA in HObLC and SaOS-2 cells. Furthermore, 12-O-tetradecanoylphorbol ester stimulated VEGF mRNA in a time-and concentration-dependent manner. The VEGF mRNA expression induced by 1,25-(OH)2D3 was completely inhibited by H-7, but only partially by staurosporine. We have demonstrated that PTH, IGF-I, and most potently 1,25-(OH)2D3 stimulate the mRNA expression and secretion of VEGF in human osteoblast-like cells, suggesting that one of the anabolic effects of 1,25-(OH)2D3 on skeletal tissue may be mediated by VEGF produced by osteoblasts.
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PMID:Increase of vascular endothelial growth factor mRNA expression by 1,25-dihydroxyvitamin D3 in human osteoblast-like cells. 899 78

The insulin-like growth factor-I receptor (IGF-IR) is involved in tumorigenesis. The aim of the present study was to investigate whether the IGF-IR is a physiological target for p53 in osteosarcoma cells. The p53-induced regulation of IGF-IR levels was studied in a tetracycline-regulated expression system. When expressed in Saos-2, osteosarcoma cells that lack p53, wild-type p53 decreased, whereas mutated p53 increased IGF-IR expression, and IGF-I-induced tyrosine phosphorylation of the IGF-IR. Similarly, wild-type p53 decreased IGF-I-induced tyrosine phosphorylation of IRS-1. A functional and physical interaction between p53 and Sp1, in the regulation of the IGF-R, was studied in osteosarcoma cells. Expression of p53 decreased IGF-IR promoter activity, whereas no effect on promoter activity was seen by Sp1 expressed alone. However, Sp1 counteracted the inhibitory effect of p53 on IGF-IR promoter activity in a dose-dependent manner. Furthermore, wild-type and mutated p53 were coimmunoprecipitated with Sp1, indicating a physical interaction between p53 and Sp1. In conclusion, p53 regulates IGF-IR expression, as reflected by a reduction in IGF-IR protein and a parallel reduction in IGF-I-induced tyrosine phosphorylation of the IGF-IR and IRS-1 in an osteosarcoma cell line. These data indicate that the IGF-I receptor is a physiological target for p53 in osteosarcoma cells. Furthermore, data supporting an interaction between p53 and Sp1 in the regulation of the promoter activity of IGF-IR are presented.
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PMID:p53 regulates insulin-like growth factor-I (IGF-I) receptor expression and IGF-I-induced tyrosine phosphorylation in an osteosarcoma cell line: interaction between p53 and Sp1. 949 43

The mitogen-activated protein (MAP) kinases (p44mapk and p42mapk), also known as extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), are activated in response to a variety of extracellular signals, including growth factors, hormones and, neurotransmitters. We have investigated MAP kinase signal transduction pathways in normal human osteoblastic cells. Normal human bone marrow stromal (HBMS), osteoblastic (HOB), and human (TE85, MG-63, SaOS-2), rat (ROS 17/2.8, UMR-106) and mouse (MC3T3-E1) osteoblastic cell lines contained immunodetectable p44mapk/ERK1 and p42mapk/ERK2. MAP kinase activity was measured by 'in-gel' assay using myelin basic protein as the substrate. Mainly ERK2 was rapidly activated (within 10 min) by bFGF, IGF-I and PDGF-BB in normal HOB, HBMS and human osteosarcoma cells, whereas both ERK1 and ERK2 were activated by growth factors in rat osteoblast-like cell lines, ROS 17/2.8 and UMR-106. The ERK1 activation was greater than the ERK2 in ROS 17/2.8 cells. Furthermore, ERK2 was also activated by bFGF and PDGF-BB in the mouse osteoblastic cell line, MC3T3-E1. This is the first demonstration of inter-species differences in the activation of MAP kinases in osteoblastic cells. Cyclic AMP derivatives or cAMP generating agents such as PTH and forskolin inhibited ERK2 activation by bFGF and PDGF-BB suggesting a 'cross-talk' between the two different signalling pathways activated by receptor tyrosine kinases and cAMP-dependent protein kinase. The accumulated results also suggest that the MAP kinases may be involved in mediating mitogenic and other biological actions of bFGF, IGF-I and PDGF-BB in normal human osteoblastic and bone marrow stromal cells.
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PMID:Identification and activation of mitogen-activated protein (MAP) kinase in normal human osteoblastic and bone marrow stromal cells: attenuation of MAP kinase activation by cAMP, parathyroid hormone and forskolin. 954 82

A 6.5-year-old male with normal linear growth, despite septo-optic dysplasia, panhypopituitarism and a deficient GH/IGF axis, is presented. In addition to measuring IGF-I, IGF-II and IGFBP-3, serum IGFBP-1, -2, -4 and -5 were measured. A human osteosarcoma cell line was used to assess growth-promoting activity in the patient's serum. The role of leptin in linear growth in this case was investigated. There was no evidence for hyperinsulinism or hyperandrogenism. GH was undetectable upon multiple stimulation. GHBP was elevated. Serum IGF-I (25 microg/l), IGF-II (194 microg/l), IGFBP-3 (0.4 mg/l), and IGFBP-5 (87 microg/l) levels were low compared to age-matched prepubertal children. Serum IGFBP-4 level was normal. Molecular size of IGF-II in the patient's serum was normal, suggesting normal IGF-II bioavailability. Human osteosarcoma cell proliferation in response to the patient's serum was similar to sera from age-matched normal controls. Leptin levels were markedly elevated. Osteoblast cell proliferation was not stimulated by leptin. The data demonstrate that normal growth and osteoblast cell proliferation in this patient is not mediated by GH, total IGFs, insulin, or leptin, and suggest the presence of a yet unidentified growth factor or mechanism. The case offers a detailed picture of binding proteins in a case of growth without GH. It introduces osteoblast cell proliferation as a method of assessing serum growth-promoting activity in such cases. It adds IGF-II and leptin to the list of excluded growth-promoting candidates in GH-independent growth, and further demonstrates our incomplete understanding of the phenomenon of growth.
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PMID:Normal growth despite GH, IGF-I and IGF-II deficiency. 1051 93

Insulin-like growth factor-I exerts potent mitogenic effects through the type I IGF receptor, a member of the insulin receptor family, and exhibits at the same time some insulin-like metabolic activities. We have questioned whether IGF-I presents moreover a modulatory effect upon programmed cell death (PCD)(apoptosis) in serum-deprived human osteosarcoma U-2 OS cells, a cell line synthesizing IGF-II and exhibiting an increased DNA synthesis following treatment with IGF-I. U-2 OS cells were cultured in a medium containing 0.8% FCS and growth arrest was induced by transfer to serum-free growth conditions. PCD was measured using a commercially available DNA degradation ELISA while viable cell numbers were counted microscopically after trypan exclusion to estimate net proliferative activity. Following serum withdrawal for 24 hrs., the level of PCD in U-2 OS cells was increased six-fold while cell number was reduced by approximately 35% compared to cells grown in the presence of 15% serum. Incubation with recombinant human IGF-I for 24 hrs. caused a dose-dependent inhibition of the level of programmed cell death. Co-incubation with an IGF-I receptor monoclonal antibody (alphaIR3) dose-dependently blocked the effects of 10 ng/ml IGF-I on PCD, with an ED50 of 1-10 ng/ml of alphaIR3 immunoglobulin. Conversely IGF-1 provoked a significant cell number increase, an effect blocked by addition of alphaIR3. The addition of an inhibitor of caspase 1 (ICE) had little effect on PCD but resulted in a net increase in the number of viable cells. In summary, IGF-I treatment of U-2 OS cells at the same time inhibits the induced programmed cell death and increases the cell number, effects which are blocked by addition of IGF-I receptor antibodies. These data support the hypothesis that IGF-I affects cells in a dual way, both by enhancing proliferative responses and by suppressing programmed cell death. The differential response between PCD and cell number to ICE inhibitors suggests the existence of independent control systems for these processes although the role of IGF-I in this study has yet to be determined.
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PMID:Insulin-like growth factor-I inhibits the progression of human U-2 OS osteosarcoma cells towards programmed cell death through interaction with the IGF-I receptor. 1072 73

The current studies were intended to determine whether the anabolic effects of calcitonin (CT) on human osteoblast-line cells were (1) unique to osteosarcoma cells or also evident in osteoblast-line cells derived from normal human bone; and/or (2) associated with effects on several insulin-like growth factor (IGF) system components. Preliminary studies identified several osteoblastic cell lines, derived from normal human bone, which showed calcitonindependent increases in cell proliferation, alkaline phosphatase activity, and/or (45)Ca uptake (P < 0.05-P < 0.001). Two of these cell lines-(human vertebrae) HBV-155 and HBV-163-were included with the human osteosarcoma cell line, SaOS-2, in most of our subsequent studies of calcitonin effects on selected IGF system components: IGF-II, IGF-I, and IGF binding proteins -3, -4, and -5. The results of those studies revealed that a 48 hour exposure to salmon CT caused a dose-dependent (0.03-3 mU/ml) increase in the net extracellular level of IGF-II (r = 0.96, P < 0.01) in serum-free cultures of SaOS-2 cells, with a maximal 60% increase at the highest tested dose (P < 0.02). Similar effects were seen with HBV-163 cells (r = 0.90, P < 0.01) and HBV-155 cells (r = 0.55, P < 0.02). The effect of calcitonin on the extracellular level of IGF-II was biphasic with respect to time: it decreased at 6 hours (P < 0.005 and P < 0.001, for SaOS-2 cells and HBV-163 cells, respectively) and increased at 24 hours (P < 0.02 and P < 0.05). These calcitonin-dependent increases in the extracellular level of IGF-II were associated with parallel increases in IGF-I (P < 0.005 for SaOS-2 cells and P < 0.03 for HBV-163 cells), but calcitonin did not affect the extracellular level of transforming growth factor (TGF)-beta. The calcitonin-dependent changes in IGF-II were not associated with changes in the extracellular levels of IGF binding proteins -3, -4, or -5. Finally, our studies showed that two other members of the CT superfamily-CT gene-related peptide and amylin-did not mimic the effect of CT to increase the extracellular level of IGF-II. Together, these data demonstrate that human osteoblast-line cells derived from normal human bone can respond to CT, and that those responses can include CT dose- and time-dependent increases in the extracellular levels of IGF-I and IGF-II.</hea
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PMID:Calcitonin increases the concentration of insulin-like growth factors in serum-free cultures of human osteoblast-line cells. 1095 80


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