UMLS:C0029463 - FACTA Search

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Query: UMLS:C0029463 (osteosarcoma)
16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that the actions of IGF-II in bone are determined not only by its concentration, but also by the concentration of IGFBP-4 as well as other IGFBPs. In this study, we sought to determine by Western ligand blotting the effects of growth hormone, IGF-I and IGF-II on the production of IGFBP-3 and IGFBP-4 in TE89 human osteosarcoma cells and in untransformed normal human bone cells derived from rib. Human growth hormone at 10 micrograms/l decreased the amount of IGFBP-4 but had no effect on the IGFBP-3 level in the conditioned medium of low density cultures of TE89 cells and human bone cells derived from rib. Human growth hormone had no effect on IGFBP-3 or IGFBP-4 levels in the conditioned medium of high density human bone cell cultures. IGF-I and IGF-II, which increased human bone cell proliferation, decreased the level of IGFBP-4 (30% of control at 100 micrograms/l IGF-I and IGF-II) but increased the level of IGFBP-3 (3-10 fold at 100 micrograms/l IGF-I and IGF-II) after 48 h of treatment in the conditioned medium of both low and high density TE89 cell cultures. Similar changes in IGFBP-3 and IGFBP-4 levels were also seen in the conditioned medium of human bone cells derived from rib after treatment with IGF-I and IGF-II. Studies to determine the underlying molecular mechanisms by which IGF-II decreased the amount of IGFBP-4 in the conditioned medium revealed that IGF-II decreased the IGFBP-4 mRNA abundance and increased the IGFBP-3 mRNA abundance in human bone cells. Based on the above findings, we conclude that the production of both IGFBP-3 and IGFBP-4 is regulated in bone cells and that local and systemic agents may modulate the responsiveness of bone cells to IGFs by regulated secretion of IGFBP-3 and IGFBP-4.
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PMID:Studies on regulation of insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-4 production in human bone cells. 128 79

In this study we report the preparation of a human osteosarcoma cell cDNA library and describe the isolation and sequence determination of a clone encoding the complete sequence of a novel human insulin-like growth factor (IGF)-binding protein (hIGFBP-4). Previous work indicated that hIGFBP-4 is the predominant IGFBP expressed by human osteoblast-like cells, and that IGFBP-4 binds and inhibits the mitogenic activities of IGF-I and IGF-II. Sequence determination revealed that hIGFBP-4 is a unique gene product with significant amino- and carboxy-terminal sequence similarity to three other known IGFBPs. Identical alignment of 18 cysteines in IGFBP-4 and the three other IGFBPs is a key structural feature of this protein family. In vitro studies of human osteoblast-like cells suggest that PTH regulates the expression of hIGFBP-4 and that the PTH effect is mediated through a cAMP mechanism. hIGFBP-4 mRNA was also expressed in skin fibroblasts, and thus, this inhibitory IGFBP could be an important physiological regulator of IGF actions in bone cells and other cell types as well.
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PMID:Inhibitory insulin-like growth factor-binding protein: cloning, complete sequence, and physiological regulation. 170 25

Our previous studies have shown that insulin-like growth factor-II (IGF-II) is an important autocrine/paracrine regulator of human bone cell proliferation. In this study, we sought to look at the regulation of IGF-II production by human bone cells since IGF-II synthesis is a key variable that regulates the actions of IGF-II at a local site of bone. For studies of IGF-II regulation, we used TE85 human osteosarcoma cells as a model system since these cells exhibited several characteristics which are similar to that of untransformed normal human bone cells. In this study, we investigated the effects of agents which increase intracellular cAMP (forskolin, isobutylmethyl xanthine and prostaglandin E2) and N6,O2' dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) on the IGF-II regulatory system. It was found that these agents caused an increase in the production of an IGFBP in TE85 cells. Subsequent studies on the purification and characterization of IGFBP from DBcAMP treated TE85 cell conditioned medium revealed that the IGFBP produced by TE85 cells in response to DBcAMP treatment was identical to that of 25 kDa inhibitory IGFBP (now designated as IGFBP-4) purified from TE89 human bone cells based on: 1) N-terminal amino acid sequence, 2) amino acid composition, 3) molecular weight and 4) inhibitory actions on basal and IGF-II induced bone cell proliferation. In addition, forskolin and DBcAMP also caused a dose dependent decrease in the production of IGF-II. Consistent with these results, DBcAMP and agents which increase intracellular cAMP inhibited TE85 cell proliferation in a dose dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence that the inhibition of TE85 human bone cell proliferation by agents which stimulate cAMP production may in part be mediated by changes in the IGF-II regulatory system. 172 35

Previous studies have shown that the actions of insulin-like growth factor-II (IGF-II) in bone are determined by both its concentration and the concentrations of the IGF-binding proteins (IGFBPs). As IGFBP concentrations may be regulated not only at the level of production, but also at the level of degradation, IGFBP proteases may be an important component of the IGF-II regulatory system. In this study, we have identified IGFBP-4 and IGFBP-5 protease activity in the conditioned medium (CM) of the human osteosarcoma U2 cell line (U2OS) and untransformed normal human bone cell (HBC) derived from skull. Proteolysis of the 29-kilodalton (kDa) [125I]IGFBP-5 produced an 18- to 20-kDa fragment of IGFBP-5, and 25 kDa [125I]IGFBP-4 yielded two lower mol wt fragments in the presence of IGF-II. CM from IGF-II-treated U2OS and normal HBC cultures exhibited decreased IGFBP-5 proteolytic activity compared to control cultures. In contrast, CM from IGF-II-treated HBC cultures had increased proteolytic activity against IGFBP-4. To determine the mechanisms by which IGF-II modulates IGFBP-4 and -5 proteolytic activity, CM from control U2OS cell culture was incubated with [125I]IGFBP-4 or -5 in the presence of various concentrations of IGF-II and IGF analogs under cell-free conditions. It was found that exogenous IGF-II stimulated IGFBP-4 proteolysis, but IGF analogs that had no or extremely low affinity to IGFBP-4 failed to induce IGFBP-4 proteolysis. On the contrary, exogenous IGF-II had no effect on IGFBP-5 proteolysis in cell-free U2OS CM. Both IGFBP-4 and IGFBP-5 proteolytic activities were inhibited by aprotinin, zinc chloride, and EDTA and eluted as a single major peak between mol wt markers of 160 and 67 kDa upon gel filtration. Based on the findings that HBCs in culture produce a protease(s) capable of cleaving both IGFBP-4 and IGFBP-5 and that IGF-II can promote or inhibit proteolytic degradation of IGFBP-4 and IGFBP-5, respectively, it is proposed that IGFBP protease(s) may be an important modulator of IGF activity in bone.
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PMID:Evidence that human bone cells in culture produce insulin-like growth factor-binding protein-4 and -5 proteases. 750 11

Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) are thought to play an important role in the regulation of bone metabolism. In the present study, we investigated the effect of 1,25-dihydroxyvitamin D(3) [1,25-(OH)2D3] on the expression and secretion of IGFBPs in human osteoblast-like osteosarcoma cells (MG63) and untransformed human bone-derived cells in vitro. Northern blot analysis revealed that 1,25-(OH)2D3 (10(-8) mol/L) increased IGFBP-4 messenger RNA maximally 11-fold over control level in MG63 cells (after 24 h treatment) and 2.8-fold in human bone-derived cells (at 10(-10) mol/L). 1,25-(OH)2D3 increased secretion of IGFBP-4 2- and 3-fold, respectively, in MG63 cells and in human bone-derived cells. In normal human bone-derived cells, 1,25-(OH)2D3 also stimulated messenger RNA expression (3.9-fold) and the secretion of IGFBP-3 (2.2-fold). 1,25-(OH)2D3 also increased IGFBP-4 expression in skin fibroblasts but not in hepatocellular carcinoma cells. Consistent with these in vitro findings, treatment of human subjects with high doses of oral 1,25-(OH)2D3 (2-3 micrograms/day) for psoriasis resulted in a significant increase in serum IGFBP-4 concentration compared with pretreatment levels. Our observations present direct evidence that 1,25-(OH)2D3 plays an important role in the regulation of IGFBP secretion in vitro and in vivo.
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PMID:1,25-Dihydroxyvitamin D3 increases secretion of insulin-like growth factor binding protein-4 (IGFBP-4) by human osteoblast-like cells in vitro and elevates IGFBP-4 serum levels in vivo. 752 41

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

Insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) is secreted by a variety of osteoblastic cells and appears to be an integral component of bone cell physiology. We have previously reported that normal human osteoblast-like (hOB) cells secrete IGFBP-4 as well as a novel IGFBP-4 protease, which requires IGF for functional activity. In this study we assessed the IGFBP-4/IGFBP-4 protease system in transformed osteoblastic cells by Western ligand blotting and cell-free IGFBP-4 protease assays. Simian virus-40-immortalized hOB cells (HOBIT), human osteosarcoma cells (TE-85), and rat osteosarcoma cells (UMR 106-01, ROS 17/2.8) secrete IGFBP-4. In contrast to the rapid and dramatic proteolysis in hOB medium, medium conditioned by these cells had no apparent IGFBP-4 protease activity when assayed with exogenous IGF-II in culture or under cell-free conditions. Assayed in the presence of exogenous protease. HOBIT cells, but not the osteosarcoma cell lines, appeared to produce a cycloheximide-sensitive inhibitor of the IGFBP-4 proteolytic reaction. Transient cell transformation induced by incubating human osteoblasts transfected with a temperature-sensitive mutant of simian virus-40 T-antigen at the permissive temperature or by treating hOB cells with phorbol ester tumor promoters also resulted in inhibition of IGF-dependent IGFBP-4 proteolysis. Inhibition was observed if phorbol ester was added to the cultures at the time of medium change or after the protease had been expressed and secreted. Differences in IGFBP-4 proteolysis could not be accounted for by changes in IGFBP-4 messenger RNA expression or substrate levels. These data suggest that transformation is associated with alterations in the IGFBP-4/IGFBP-4 protease system in osteoblastic cells. Normal human osteoblasts secrete an IGF-dependent IGFBP-4 protease. The induction of an inhibitor of the IGF-dependent IGFBP-4 proteolytic reaction may be associated with early transformation processes. Fully tumorigenic bone cells expressed neither IGFBP-4 protease nor protease inhibitor activity.
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PMID:Alterations in insulin-like growth factor (IGF)-dependent IGF-binding protein-4 proteolysis in transformed osteoblastic cells. 753 97

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

Endothelial cells regulate the passage of insulin-like growth factors (IGFs) or IGFs complexed to IGF-binding proteins (IGFBPs) from plasma to the extravascular space, and in addition respond to plasma and tissue IGFs. The IGFBPs are thought to determine the availability and localization of IGFs to tissues, and to inhibit or potentiate their biological activity. Because of the potential importance of the IGF system in endothelial cell pathophysiology, and because IGFBPs modulate IGF action, we have characterized the IGFBPs synthesized by a clonal endothelial cell line (BPE-1) established from bovine parathyroid microvessels. The only IGFBPs identified by ligand blotting in media conditioned by BPE-1 cells were N-glycosylated 28 kilodalton and non-N-glycosylated 24 kilodalton IGFBP-4 species. Both forms were immunoprecipitated by antibodies to human IGFBP-4. Northern blot hybridization of BPE-1 RNA identified messenger RNAs for IGFBP-4 and IGFBP-6, but not for IGFBP-1, 2, 3, or 5. Agents that increase cAMP including forskolin, (Bu)2cAMP, isobutyl-methylxanthine, and histamine increased IGFBP-4 and IGFBP-4 messenger RNA in BPE-1 cells 2- to 5-fold and 2- to 3-fold, respectively, similar to results previously reported in human osteosarcoma cells and fibroblasts. Increased IGFBP-4 was detected in BPE-1 media 6 h after forskolin addition and was maximal after 24 h. Maximal stimulation (6- to 9-fold) was observed with 1-30 microM forskolin. IGFBP-4 also was the predominant IGFBP synthesized by two other endothelial cell lines, a clonal cell line established from bovine bone microvessels, and a polyclonal cell line established from calf pulmonary artery. Further study is required to determine the role of endothelial cell IGFBP-4 on endothelium and adjacent cells, and on the transport of IGFs from plasma to specific subendothelial sites.
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PMID:Cyclic adenosine monophosphate stimulates insulin-like growth factor binding protein-4 and its messenger ribonucleic acid in a clonal endothelial cell line. 768 82

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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