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)

Vanadium is a trace element present in practically all cells in plants and animals. It exerts interesting actions in living systems. At pharmacological doses, vanadium compounds display relevant biological actions such as mimicking insulin and growth factors as well as having osteogenic activity. Some vanadium compounds also show antitumoral properties. The importance of vanadium in bone arises from the studies developed to establish the essentiality of this element in animals and humans. Bone tissue, where the element seems to play an important role, accumulates great amounts of vanadium. This paper reviews the physiology of osteoblasts, the involvement of different growth factors on bone development, and the effects of vanadium derivatives on the skeletal system of animal models and bone-related cells. Two cellular lines are discussed in particular; one derived from a rat osteosarcoma (UMR106) and the other is a nontransformed osteoblast cell line (MC3T3-E1). The effects of different growth factors and their mechanisms of action in these cellular lines are reviewed. These models of osteoblasts are especially useful in understanding the intracellular signaling pathways of vanadium derivatives in hard tissues. Vanadium uses an intricate interplay of intracellular mechanisms to exert different biochemical and pharmacological actions. The effects of vanadium derivatives on some cellular signaling pathways related to insulin are compiled in this review. The comprehension of these intracellular signaling pathways may facilitate the design of vanadium compounds with promising therapeutic applications as well as the understanding of secondary side effects derived from the use of vanadium as a therapeutic agent.
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PMID:Vanadium and bone development: putative signaling pathways. 1699 31

The insulin-like growth factors I and II (IGF-I, IGF-II), their receptors, and high affinity binding proteins (IGFBPs) represent a family of cellular modulators that play essential roles in the development and differentiation of cells and tissues including the skeleton. Recently, the human osteosarcoma cell line HOS 58 cells were used as an in vitro model of osteoblast differentiation characterized by (i) a rapid proliferation rate in low-density cells that decreased continuously with time of culture and (ii) an increasing secretion of matrix proteins during their in vitro differentiation. In the present paper, HOS 58 cells with low cell density at early time points of the in vitro differentiation (i) displayed a low expression of IGF-I and -II; (ii) synthesized low levels of IGFBP-2, -3, -4, and -5, but (iii) showed high expression levels of both the type I and II IGF receptors. During the in vitro differentiation of HOS 58 cells, IGF-I and -II expressions increased continuously in parallel with an upregulation of IGFBP-2, -3, -4, and -5 whereas the IGF-I receptor and IGF-II/M6P receptor mRNA were downregulated. In conclusion, the high proliferative activity in low cell density HOS 58 cells was associated with high mRNA levels of the IGF-IR, but low concentrations of IGFBP-2. The rate of proliferation of HOS 58 cells continuously decreased during cultivation in parallel with a decline in IGF-IR expression, but increase of mitoinhibitory IGFBP-2. These data are indicative for a role of the IGF axis during the in vitro differentiation of HOS 58 cells.
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PMID:Alteration of the insulin-like growth factor axis during in vitro differentiation of the human osteosarcoma cell line HOS 58. 1737 31

Most patients with type 2 diabetes mellitus will eventually require insulin therapy to achieve or maintain adequate glycaemic control. The introduction of insulin analogues, with pharmacokinetics that more closely mimic endogenous insulin secretion, has made physiologic insulin replacement easier to achieve for many patients. However, there are also concerns regarding alteration of binding affinities for the insulin receptor (IR) or insulin-like growth factor-1 receptor (IGF-1R) may increase the mitogenic potential of some analogues. Therefore, this article will review the relevant preclinical and clinical data to assess the mitogenic potential of insulin glargine, a basal insulin analogue, compared with regular human insulin (RHI). Searches of the PubMed database were performed using terms that included 'IR,' 'insulin-like growth factor-1,' 'IGF-1R,' 'type 2 diabetes mellitus,' and 'insulin glargine.' Original articles and reviews of published literature were retrieved and reviewed. Although one study reported increased binding affinity of insulin glargine for the IGF-1R and increased mitogenic potential in cells with excess IGF-1Rs (Saos/B10 osteosarcoma cells), most in vitro binding-affinity and cell-culture studies have demonstrated behaviour of insulin glargine comparable to that of RHI for both IR and IGF-1R binding, insulin signalling, and metabolic and mitogenic potential.Currently published in vivo carcinogenic studies and human clinical trial data have shown that insulin glargine is not associated with increased risk for either cancer or the development or progression of diabetic retinopathy.
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PMID:Insulin glargine and receptor-mediated signalling: clinical implications in treating type 2 diabetes. 1792 76

The aim of the study was to investigate if the insulin analogue glargine, with an increased affinity for the IGF-I receptor (IGF-IR), affects the cell growth to a larger extent than human insulin in malignant cells expressing IGF-IRs. The breast cancer cell lines MCF-7 and SKBR-3, and the osteosarcoma cell line SaOS-2 were used. Gene expression was determined by real-time RT-PCR and receptor protein quantified by ELISAs. Receptor phosphorylation was assessed by immunoprecipitation and Western blot. Mitogenic effect was determined as (3)H-thymidine incorporation into DNA. The gene expression of insulin receptor (IR) varied between 4.3-7.5 x 10(-3) and the expression of IGF-IR between 7.7-147.7 x 10(-3) in relation to GAPDH (glyceraldehyde-3-phosphate dehydrogenase). Insulin receptor and IGF-IR protein varied between 2.0-4.1 ng/mg protein and 2.0-40.4 ng/mg protein, respectively. The IGF-IR was phosphorylated by IGF-I at a concentration of 10(-10)-10(-9) M. All three polypeptides stimulated DNA synthesis in MCF-7, SKBR-3, and SaOS-2 cells. SaOS-2 cells were more sensitive to IGF-I than to insulin and glargine. MCF-7 cells were more sensitive to des(1-3)IGF-I than to IGF-I. In SKBR-3 and SaOS-2 cells, glargine tended to be more potent than human insulin to stimulate DNA synthesis. Our results suggest that glargine, compared to human insulin, has little or no increased mitogenic effect in malignant cells expressing IGF-IRs.
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PMID:Mitogenic effect of the insulin analogue glargine in malignant cells in comparison with insulin and IGF-I. 1839 72

Insulin-like growth factor binding protein (IGFBP)-6 has been reported to inhibit differentiation of myoblasts and osteoblasts. In the current study, we explored the mechanisms underlying IGFBP-6 effects on osteoblast differentiation. During MC3T3-E1 osteoblast differentiation, we found that IGFBP-6 protein was down-regulated. Overexpression of IGFBP-6 in MC3T3-E1 and human bone cells inhibited nodule formation, osteocalcin mRNA expression and ALP activity. Furthermore, accumulation of IGFBP-6 in the culture media was not required for any of these effects suggesting that IGFBP-6 suppressed osteoblast differentiation by an intracellular mechanism. A yeast two-hybrid screen of an osteosarcoma library was conducted to identify intracellular binding partners to account for IGFBP-6 inhibitory effects on osteoblast differentiation. LIM mineralizing protein (LMP-1) was identified as a high affinity IGFBP-6 binding partner. Physical interaction between IGFBP-6 and LMP-1 was confirmed by co-immunoprecipitation. Fluorescent protein fusion constructs for LMP-1 and IGFBP-6 were transiently transfected into osteoblasts to provide evidence of subcellular locations for each protein. Coexpression of LMP-1-GFP and IGFBP-6-RFP resulted in overlapping subcellular localization of LMP-1 and IGFBP-6. To determine if there was a functional association of IGFBP-6 and LMP-1 as well as a physical association, we studied the effect of IGFBP-6, LMP-1 and their combination on type I procollagen promoter activity. LMP-1 increased promoter activity while IGFBP-6 reduced promoter activity, and coexpression of LMP-1 with IGFBP-6 abrogated IGFBP-6 suppression. These studies provide evidence that overexpression of IGFBP-6 suppresses human and murine osteoblast differentiation, that IGFBP-6 and LMP-1 physically interact, and supports the conclusion that this interaction may be functionally relevant.
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PMID:Potential involvement of the interaction between insulin-like growth factor binding protein (IGFBP)-6 and LIM mineralization protein (LMP)-1 in regulating osteoblast differentiation. 1839 33

Insulin-like growth factor binding protein 5 (IGFBP5) is expressed in many cell types including osteoblasts and modulates IGF activities. IGFBP5 may affect osteoblasts and bone formation, in part by mechanisms independent of binding IGFs. The highly conserved IGFBP5 proximal promoter within 100 nucleotides of the start of transcription contains functional cis regulatory elements for C/EBP, Myb and AP-2. We report evidence for a functional Nuclear Factor I (NFI) cis element that mediates activation or repression of IGFBP5 transcription by the NFI gene family. All four NFI genes were expressed in human osteoblast cultures and osteosarcoma cell lines. Co-transfection with human IGFBP5 promoter luciferase reporter and murine Nfi expression vectors showed that Nfib was the most active in stimulating transcription. Nfix was less active and Nfia and Nfic were inhibitory. Knockdown of NFIB and NFIC expression using siRNA decreased and increased IGFBP5 expression, respectively. Analysis of IGFBP5 promoter deletion and mutation reporter constructs identified a functional NFI cis element. All four NFI proteins bound the NFI site in electrophoretic mobility shift experiments and NFIB bound in chromatin immunoprecipitation assays. Results suggest that NFI proteins are important regulators of IGFBP5 expression in human osteoblasts and thus in modulating IGFBP5 functions in bone.
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PMID:Nuclear factor I transcription factors regulate IGF binding protein 5 gene transcription in human osteoblasts. 1880 17

Insulin-like growth factor-II mRNA binding protein 3 (IMP3) is one of the RNA binding proteins implicated in mRNA localization and translational control. It is expressed during embryogenesis, as well as in some malignant tumors. Recent studies suggest its potential use as a prognostic factor or as a therapeutic target in malignancy. Using tissue microarray, we examined the immunohistochemical staining of IMP3 in osteosarcoma cases to evaluate whether it could serve as a prognostic biomarker. In a tissue microarray analysis of 47 paraffin-embedded osteosarcoma cases, 8 (17.02%) were positive for IMP3 immunostaining, and IMP3 expression was correlated with tumor metastasis (p = 0.020). IMP3 expression was independent of survival, tumor site, histologic type, age, and gender. These results suggest that IMP3 could be used as an independent prognostic factor for cases of osteosarcoma with a high potential for metastasis.
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PMID:Expression of insulin-like growth factor-II mRNA binding protein 3 (IMP3) in osteosarcoma. 1919 21

The goal of diabetes mellitus treatment is to maintain long-term near-normoglycaemia to prevent the onset or progression of long-term complications. In order to achieve tight glycaemic control and improve the quality of life for diabetic patients, a number of novel insulin preparations, insulin analogues, have been constructed thanks to recombinant DNA technologies and advanced protein chemistry. Because structurally modified insulins may differ from human insulin not only in metabolic but also in mitogenic potencies there were concerns raised about the possibility of increased insulin analogue proliferative action or tumourigenesis. In vitro and in vivo studies on insulin analogues in comparison to endogenous insulin have been performed to closely monitor the insulin analogue action profiles. Insulin glargine was the only one presenting a significant increase in affinity to insulin-like growth factor type 1 (IGF-1) receptor. However, there was controversy regarding the safety of insulin glargine use because of its potential risk of mitogenicity but it proved to be true only for human osteosarcoma cells Saos/B10. Outcomes of the studies performed on lines other than cancer cells and on animals did not present any increased mitogenic activity nor mitogenic potency of insulin glargine in comparison to human insulin.
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PMID:Mitogenic potency of insulin glargine. 1922 3

Multiple advantages-including the short generation time, large numbers of fertilized eggs, low cost of cultivation and easy maintenance favor the use of fish as bioreactors for the production of pharmaceutical proteins. In the present study, zebrafish eggs were used as bioreactors to produce mature tilapia insulin-like growth factors (IGFs) proteins using the oocyte-specific zona pellucida (zp3) promoter. The chimeric expression plasmids, pT2-ZP-tIGFs-IRES-hrGFP, in which hrGFP was used as reporter of tilapia IGFs expression, were designed to established Tg (ZP:tIGFs:hrGFP) transgenic lines for the expression of tilapia IGF-1 and IGF-2. Recombinant tilapia IGF-1 and IGF-2 were expressed as soluble forms in cytoplasm of fertilized eggs. The content level of tilapia IGF-1 and IGF-2 were 6.5 and 5.0% of the soluble protein, respectively. Using a simple Ni-NTA affinity chromatography purification process, 0.58 and 0.49 mg of purified tilapia IGF-1 and IGF-2 were obtained, respectively, from 650 fertilized eggs. The biological activity of the purified tilapia IGF-1 and IGF-2 was confirmed via a colorimetric bioassay to monitor the growth stimulation of zebrafish embryonic cells (ZF4), tilapia ovary cells (TO-2) and human osteosarcoma epithelial cells (U2OS). These results demonstrate that the use of zebrafish eggs as bioreactors is a promising approach for the production of biological recombinant proteins.
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PMID:Zebrafish eggs used as bioreactors for the production of bioactive tilapia insulin-like growth factors. 2037 20

Osteosarcoma is the most common type of malignant bone cancer, accounting for 35% of primary bone malignancies. Because cancer cells utilize glucose as their primary energy substrate, the expression and regulation of glucose transporters (GLUT) may be important in tumor development and progression. GLUT expression has not been studied previously in human osteosarcoma cell lines. Furthermore, although insulin and insulin-like growth factor (IGF-I) play an important role in cell proliferation and tumor progression, the role of these hormones on GLUT expression and glucose uptake, and their possible relation to osteosarcoma, have also not been studied. We determined the effect of insulin and IGF-I on GLUT expression and glucose transport in three well-characterized human osteosarcoma cell lines (MG-63, SaOs-2, and U2-Os) using immunocytochemical, RT-PCR and functional kinetic analyses. Furthermore we also studied GLUT isoform expression in osteosarcoma primary tumors and metastases by in situ hybridization and immunohistochemical analyses. RT-PCR and immunostaining show that GLUT1 is the main isoform expressed in the cell lines and tissues studied, respectively. Immunocytochemical analysis shows that although insulin does not affect levels of GLUT1 expression it does induce a translocation of the transporter to the plasma membrane. This translocation is associated with increased transport of glucose into the cell. GLUT1 is the main glucose transporter expressed in osteosarcoma, furthermore, this transporter is regulated by insulin in human MG-63 cells. One possible mechanism through which insulin is involved in cancer progression is by increasing the amount of glucose available to the cancer cell.
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PMID:Insulin regulates GLUT1-mediated glucose transport in MG-63 human osteosarcoma cells. 2132 33


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