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)

Recent clinical studies suggest that progesterone may be involved in the regulation of bone turnover and could promote bone formation. This study was undertaken to evaluate whether progesterone and promegestone (a 19 nor-PG derivative) may have a direct effect on human bone cells and, if so, whether growth factor production could be involved in promoting this effect. The osteosarcoma cell line TE85 and untransformed normal human osteoblastic cells derived from iliac crest were used as in vitro model systems. Progesterone and promegestone were found to significantly increase [3H]thymidine incorporation in TE85 cells in a dose-dependent manner at concentrations ranging from 10(-12) to 10(-8) mol/l after four days of cultivation (p less than 0.01, ANOVA). Consistent with this response in the TE85 cells, progesterone and promegestone increased cell number in human osteoblastic cells after six days of treatment (p less than 0.05, ANOVA). To determine whether this effect on cell proliferation was mediated by the insulin-like growth factor (IGF) regulatory system, the levels of IGF-1, IGF-2 and IGF binding protein (IGFBP) were measured in the conditioned media of both TE85 and human osteoblast cells. While no significant changes in IGF-1 levels were found in the conditioned media of progesterone and promegestone treated cultures, progesterone and promegestone at the concentration of 5 nmol/l significantly increased IGF-2 levels 2.4 and 1.5-fold respectively, at 48 h in the conditioned medium of TE85 cells as compared to control. Similarly, a 4.1 and 1.9-fold increase in IGF-2 levels was found upon treatment with progesterone and promegestone in human osteoblastic cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Progesterone and promegestone stimulate human bone cell proliferation and insulin-like growth factor-2 production. 137

The influence of a human insulin-like growth factor binding protein, hIGFBP-1, on the action of IGFs on human osteosarcoma cells was examined. hIGFBP-1 was found to block binding of IGFs to their receptors on MG-63 cells and subsequent IGF stimulation of DNA synthesis. Concurrent incubation of hIGFBP-1 with either 125I-IGF-I or 125I-IGF-II prevented the binding of both 125I-IGFs to cells in a dose-dependent manner. hIGFBP-1 inhibition of IGF binding occurred similarly under both 4 degrees and 37 degrees C conditions. Additionally, hIGFBP-1 facilitated the dissociation of IGFs bound to cells. The inhibitory effect of hIGFBP-1 on IGF-1 mediated 3H-thymidine incorporation into DNA was dose dependent. hIGFBP-1 did not inhibit binding to or stimulation of growth in MG-63 cells by des3-IGF-1, an IGF-I analog with a 100-fold less affinity for hIGFBP-I. This confirmed that hIGFBP-1 competed for IGF receptor binding sites on MG-63. Since hIGFBP-1 did not bind to cells, inhibition of IGF action was indirect, presumably through the formation of extracellular soluble bioinactive IGF-BP complexes.
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PMID:Insulin-like growth factor binding protein (IGFBP) inhibits IGF action on human osteosarcoma cells. 172 Oct 71

Two insulin-like growth factor (IGF) receptors, the type I and type II IGF receptors, have been described. While substantial evidence indicates that the type I receptor is involved in the regulation of cell division, it is uncertain if the type II receptor also mediates this response. Similarly, the role of the insulin receptor in mediating DNA synthesis remains controversial. To address these questions, we used a monoclonal antibody (alpha IR-3) to specifically inhibit type I IGF receptor activity and examined the effects of this inhibition on IGF- and insulin-stimulated DNA synthesis in human fibroblasts. WI-38 human embryonic lung fibroblasts have both type I and type II IGF receptors, as determined by cross-linking [125I] IGF-I and [125I]IGF-II to monolayers of these cells. In serum-free medium both IGF-I and IGF-II stimulate DNA synthesis in WI-38 fibroblasts, with half-maximal effects occurring at 1.5 +/- 0.3 (+/- SD) and 3.4 +/- 1.4 nM, respectively. At maximally effective concentrations, however, both hormones stimulate DNA synthesis to equal levels. alpha IR-3 binds to the type I, but not the type II, IGF receptor on WI-38 cells. It also inhibits IGF binding to the type I receptor on these cells. alpha IR-3 competitively inhibited both IGF-I- and IGF-II-stimulated DNA synthesis in WI-38 cells, but had no effect on either epidermal growth factor- or platelet-derived growth factor-stimulated DNA synthesis. These results indicate that in WI-38 fibroblasts the mitogenic effects of both IGF-I and IGF-II are mediated through the type I receptor and that the type II IGF receptor is not directly involved in this response. To define the role of the insulin receptor in mediating DNA synthesis we compared the effects of alpha IR-3 on insulin-stimulated DNA synthesis in a variety of human cell lines under identical experimental conditions. With WI-38 and HEL, another human embryonic lung fibroblast cell line, alpha IR-3 competitively inhibited the mitogenic effect of insulin. However, in two other fibroblast cell lines (GM498 and HES) and an osteogenic sarcoma cell line (MG63), alpha IR-3 inhibited IGF, but not insulin-stimulated DNA synthesis. These results indicate that human cell lines differ in the receptor type through which insulin stimulates DNA synthesis and that these differences are intrinsic properties of the cell lines and are not artifacts resulting from differences in experimental conditions.
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PMID:The type II insulin-like growth factor receptor does not mediate deoxyribonucleic acid synthesis in human fibroblasts. 295 64

The processing of insulin-like growth factor I (IGF-I) by MG-63, an IGF-I-responsive human osteosarcoma cell line, has been investigated. At 37 C, the binding of [125I] IGF-I to monolayers of MG-63 cells reaches a maximum after about 1 h and slowly declines thereafter. The addition of the lysosomotropic agents methylamine, chloroquine, and monensin to the binding medium prevents the decline in [125I]IGF-I binding observed in the untreated cells and causes a 1.5- to 3-fold increase in cell-associated radioactivity after 4 h. Leupeptin, an inhibitor of lysosomal proteases, and colchicine, an inhibitor of endosomal transport, also increase cell-associated [125I]IGF-I. Three observations indicate that the increased radioactivity associated with the treated cells is the result of intracellular accumulation of the ligands and not the result of an increase in cell surface IGF binding. First, no increase in [125I]IGF-I binding is observed in cells preincubated with methylamine at 37 C but transferred to 4 C (where endocytosis is inhibited) before the addition of the radiolabeled ligands. Second, the increased radioactivity bound by methylamine-treated cells is not removed by washing the cells with dilute acid, a treatment that removes surface-bound [125I]IGF-I. Third, in leupeptin-treated cells [125I]IGF-I accumulates in a subcellular fraction with properties characteristic of lysosomes. Both alpha IR-3 (100 nM), an antibody that specifically inhibits binding to the type I IGF receptor, and high concentrations of insulin (900 nM) inhibit the accumulation of [125I]IGF-I by methylamine-treated cells, indicating that internalization of IGF-I occurs through the type I IGF receptor and not through the type II IGF receptor or the IGF-binding protein(s) that is also present on these cells. These results demonstrate that in MG-63 cells IGF-I is endocytosed via the type I IGF receptor and that the endocytosed hormone is degraded, at least in part, in lysosomes. These findings are similar to those described for the processing of insulin and other growth factors by their target cells and extend further the homology between IGF-I and these other agents.
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PMID:Receptor-mediated endocytosis and lysosomal processing of insulin-like growth factor I by mitogenically responsive cells. 296 62

Previous studies demonstrated that insulin-like growth factors (IGFs) are important autocrine and paracrine mitogens for human bone cells in vitro and that IGF binding proteins (IGFBPs) are important regulators of the biologic actions of IGFs. Thus, the actions of IGFs may be determined not only by their concentrations but also by the type and amount of IGFBPs produced by human bone cells at a local site in bone. In this study, we sought to determine the effects of dexamethasone, 1,25-(OH)2D3, and parathyroid hormone (PTH) on the secretion of IGFBP-3 in human osteosarcoma cell lines. Serum-free cultures of low- and high-alkaline phosphatase (ALP) SaOS-2, MG-63, and TE89 human osteosarcoma cells were treated for 24 or 48 h with the effectors and the conditioned media used for determination of IGFBP-3 using a radioimmunoassay. We report that (1) the basal rate of IGFBP-3 secretion (ng/mg cellular protein) was dependent upon cell type, with TE89 > low-ALP Saos-2 > MG-63 > high-ALP SaOS-2 cells, and did not correlate with either basal cell proliferation or basal cellular ALP activity; (2) dexamethasone (10(-12)-10(-7) M) inhibited IGFBP-3 secretion in a dose-dependent manner in low-ALP SaOS-2, MG-63, and TE89 cells but not in high-ALP SaOS-2 cells; (3) 1,25-(OH)2D3 (10(-11)-10(-8) M) stimulated IGFBP-3 secretion in a dose-dependent manner in MG-63, low-ALP SaOS-2, and high-ALP SaOS-2 cells, and the coaddition of TGF-beta and 1,25-(OH)2D3 increased synergistically IGFBP-3 secretion and cellular ALP activity in MG-63 cells; and (4) human PTH-(1-34) (0.1-100 ng/ml) had no significant effect on IGFBP-3 secretion in MG-63, low-ALP SaOS-2, or high-ALP SaOS-2 cells. We conclude that such agents as dexamethasone, 1,25-(OH)2D3, and PTH differentially regulate IGFBP-3 secretion in human osteosarcoma cells in vitro.
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PMID:Studies on the regulation of insulin-like growth factor binding protein 3 secretion in human osteosarcoma cells in vitro. 752 61

Bone morphogenetic proteins (BMPs) have the unique ability to convert mesenchymal cells into matrix-producing osteoblasts. To understand the mechanism(s) by which a BMP produces a multitude of effects on bone cells, we examined the effects of recombinant human osteogenic protein (OP)-1 (referred to as BMP-7) on the insulin-like growth factor (IGF) regulatory system, an important growth factor system in bone. After 48 h of treatment, OP-1 increased the level of IGF-II (3- and 2-fold, respectively, at 100 ng/ml) in the conditioned medium (CM) of SaOS-2 and TE85 human osteosarcoma cells with osteoblastic characteristics, whereas IGF-I levels were low to undetectable in the CM of either cell type. OP-1 treatment had no significant effect on the messenger RNA (mRNA) level for type 1 and type 2 IGF receptors. In TE85 and SaOS-2 cells, 100 ng/ml OP-1 increased the level of IGF binding protein (BP)-3 more than 10-fold, decreased the IGFBP-4 level by 50%, and increased the level of the 29-32.5 kDa IGFBP-5 3-fold in the CM as determined by analysis with Western ligand blot, Western immunoblot, and RIA. The effect of OP-1 on IGFBP production was time and dose dependent. The OP-1 induced changes in the levels of IGFBPs were associated with decreased IGFBP-3 and -5 protease activity (29% and 71%, respectively) and proportional changes in IGFBP mRNA levels. OP-1 increased the level of IGFBP-3 mRNA (2- and 10-fold, respectively, after 4 and 24 h of treatment at 100 ng/ml) and of IGFBP-5 mRNA (more than 5-fold after 24 h of treatment) but decreased the level of IGFBP-4 mRNA (> 50% after 24 h at 100 ng/ml). OP-1 treatment had no effect on IGFBP-4 protease activity. These results collectively demonstrate that OP-1 can act locally by modulating the IGF regulatory system, suggesting that the mitogenic/differentiative effect of OP-1 on human bone cells may in part be mediated via IGF-II by increasing its secretion, and by regulating the balance between the stimulatory (e.g. IGFBP-5) and inhibitory (e.g. IGFBP-4) classes of IGFBPs both at the level of production (mRNA) and at the level of degradation but not by up-regulating the IGF receptor.
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PMID:Regulation of insulin-like growth factor system components by osteogenic protein-1 in human bone cells. 753 81

GH exerts its biological actions on osteoblasts through a specific high affinity receptor expressed on these cells. GH receptor binding is positively modulated by a number of factors, including retinoic acid and dexamethasone, whereas fetal calf serum strongly decreases the binding. To identify responsible factors in serum, components of serum, the insulin-like growth factors (IGFs)-I and -II, and IGF binding proteins (IGFBPs)-2 and -3 were tested for a possible negative modulatory role. IGF-I and -II decreased [125I]hGH binding at an optimal concentration of 30 ng/ml for IGF-I and 100 ng/ml IGF-II, reducing the binding to 51% and 55%, respectively, of control values. A stimulation of [125I]hGH binding was observed with IGFBP-2 as well as IGFBP-3, inducing an increase to 148% and 151% of control binding at an optimal concentration of 3000 ng/ml for both peptides. The effects of all peptides were dependent on the incubation time, being significantly increased after 8 h of incubation and reaching the full effect thereafter. The effects were declined at 24 h compared with 16 h for IGFBP-2 and -3 but not for IGF-I and -II. Coincubation of the cells with IGF-I and -II and IGFBP-2 and -3 neutralized the effects of the factors alone. In conclusion, these results show that IGF-I and -II on the one hand and IGFBP-2 and -3 on the other hand exert opposite actions on [125I]hGH binding, IGFBP-2 and -3 exerting probably an IGF-independent effect. Further, IGF-I and -II decreased GH receptor messenger RNA (mRNA) levels, as quantified by a solution hybridization ribonuclease protection assay, from 8.65 +/- 1.78 attomoles (amol)/microgram DNA (control) to 2.4 +/- 0.68 and 2.16 +/- 0.92 amol/microgram DNA, respectively. IGFBP-2 increased GH receptor mRNA levels from 5.26 +/- 1.17 (control) to 13.19 +/- 3.48. Incubation with IGFBP-3 did not result in stimulation of GH receptor mRNA levels (8.59 +/- 2.91 amol/microgram DNA). This shows that the mechanism of regulation of the GH receptor is, except for IGFBP-3, at least in part on the mRNA level. Lastly, IGFBP-2 and IGFBP-3 are mitogenic for UMR-106.01 rat osteosarcoma cells, inducing an increase in cell number to 125% and 142% of control cell counts after 48 h of incubation with 1000 ng/ml IGFBP-2 and -3, whereas IGF-I, IGF-II and Long R3 IGF-I did not stimulate proliferation. IGFBP-2 and -3 potentiate hGH induced mitogenesis at low hGH concentrations of both factors, whereas at higher concentrations no such effect is observed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Insulin-like growth factor binding proteins-2 and -3 stimulate growth hormone receptor binding and mitogenesis in rat osteosarcoma cells. 754 1

Insulin-like growth factors (IGFs) are found in human circulation predominantly as part of a growth hormone (GH)-dependent complex of 125-150 kD, which is composed of three subunits: IGF-I or IGF-II, an acid stable IGF binding protein (IGFBP)-3, and an acid labile subunit (ALS). Although recent studies demonstrate that a number of cell types in culture secrete IGFs and IGFBP-3, very little is known with regard to the origin of circulating ALS. To test the hypothesis that human bone cells (HBCs), which produce abundant amounts of IGF-II and IGFBP-3, also produce ALS, we measured the IGF-I, IGF-II, IGFBP-3, and ALS levels using specific radioimmunoassays (RIAs) in the conditioned medium (CM) of untransformed normal HBCs and SaOS-2 osteosarcoma cells treated with various effectors (IGF-II, osteogenic protein-1 [OP-1, bone morphogenetic protein-7] and human GH) for 48 h. No detectable levels (< 3 ng/ml) of ALS were found in the CM of various HBC types under basal conditions. In contrast, CM collected from liver explants in culture contained significant amount of ALS prepared and assayed under identical conditions. The IGF-I level was also undetectable in the CM of various HBC types. In the IGF-II (3, 30 ng/ml)-treated HBC CM, the IGFBP-3 level was increased in a dose-dependent manner but neither IGF-I nor ALS could be detected. In the SaOS-2 cell culture, OP-1 (1, 100 ng/ml) increased both IGF-II and IGFBP-3 secretion but neither ALS nor IGF-I secretion. Treatment of HBCs with GH (1, 10, 100 ng/ml) had no significant effect on the secretion of either IGF-I, IGF-II, IGFBP-3, or ALS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence that human bone cells in culture secrete insulin-like growth factor (IGF)-II and IGF binding protein-3 but not acid-labile subunit both under basal and regulated conditions. 757 8

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

In the present study, we have sought to determine whether a given signal transduction pathway can have diverse effects on subpopulations of cells of a lineage depending upon the stage of differentiation. To test this hypothesis, we selected the cyclic adenosine monophosphate (cAMP) signal transduction pathway because of its recognized importance in mediating the actions of many hormones, e.g., parathyroid hormone which acts on the bone-forming cells, the osteoblasts. Subpopulations of human osteosarcoma SaOS-2 cells with low (LSaOS) and high (HSaOS) alkaline phosphatase (ALP) content were chosen as model systems for preosteoblasts (pre-OB) and osteoblasts (OB), respectively. Dibutyryl cyclic AMP (DBcAMP) treatment of serum free cultures produced a differential effect on the proliferation of LSaOS cells (40 +/- 5% of control at 1 mM DBcAMP, P < 0.001) compared with HSaOS cells (no statistically significant effect). The finding supports the hypothesis. Next, we sought evidence for mediation, at least in part, by the insulin-like growth factor (IGF)-II regulatory system. We report that the basal expression of IGF-II, IGF binding protein (IGFBP)-3, and IGFBP-4 was higher in LSaOS cells than in HSaOS cells with the opposite true for type I IGF receptor. DBcAMP treatment of LSaOS cells decreased IGF-II and IGFBP-3 but increased IGFBP-4 and type I IGF receptor; no effect was observed for the type II IGF receptors. DBcAMP treatment of HSaOS cells had no detectable effect on IGF-II; IGFBP-3, or type I and type II IGF receptor expression; only IGFBP-4 expression increased with DBcAMP. These observations suggest that the differential regulation of cell proliferation by the cAMP signal transduction pathway may be mediated, at least in part, by the IGF-II regulatory system.
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PMID:Dibutyryl cyclic adenosine monophosphate differentially regulates cell proliferation in low and high alkaline phosphatase SaOS-2 human osteosarcoma cells: evidence for mediation by the insulin-like growth factor-II system. 768 70


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