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)

High molecular weight urokinase-type plasminogen activator (uPA) in which proteolytic activity was inactivated (diisopropyl fluorophosphate (DFP)-uPA), its amino-terminal fragment (ATF, amino acids (aa) 1-143), and fucosylated and defucosylated growth factor domains (GFD, aa 4-43) were tested for growth-promoting effects and binding in human SaOS-2 osteosarcoma cells and U-937 lymphoma cells. DFP-uPA, ATF, and both the fucosylated and defucosylated GFD were capable of competing with 125I-ATF for binding to both SaOS-2 and U-937 cells. DFP-uPA, ATF, and fucosylated GFD were also mitogenic in SaOS-2 cells and increased cell numbers. However, defucosylated GFD was nonmitogenic in SaOS-2 cells and did not stimulate cell proliferation, even though it bound to these cells in a manner equivalent to the fucosylated GFD. A nonglycosylated high molecular weight uPA expressed and purified from Escherichia coli inhibited 125I-ATF binding to SaOS-2 cells but was also nonmitogenic. No mitogenic activity was observed in U-937 cells treated with the uPA forms capable of eliciting a mitogenic response in SaOS-2 cells. Proteolytically prepared kringle domain (aa 47-135) and low molecular weight uPA (aa 144-411) did not compete for 125I-ATF binding and did not elicit any mitogenic response in either of the cell lines tested. In addition, tissue plasminogen activator (tPA), which has been shown to be homologous to uPA in its growth factor domain and is also fucosylated, did not inhibit 125I-ATF binding nor elicit any mitogenic response. These results demonstrate that the GFD, implicated in binding to the uPA receptor, is also responsible for growth factor like activity in SaOS-2 cells and that the fucosylation at Thr18 within this domain may serve as a molecular trigger in eliciting this response.
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PMID:Structural requirements for the growth factor activity of the amino-terminal domain of urokinase. 132 Nov 37

In order to determine the mechanism by which parathyroid hormone (PTH) stimulates plasminogen activator (PA) activity in rat osteoblasts, we investigated the effect of human PTH(1-34) [hPTH(1-34)] on the synthesis of mRNAs for tissue-type PA (tPA), urokinase-type PA (uPA), and PA inhibitor-1 (PAI-1), and on release of PA activity and PAI-1 protein in both normal rat calvarial osteoblasts and UMR 106-01 osteogenic sarcoma cells. hPTH(1-34) (0.25-25 nM) decreased PAI-1 mRNA and protein, and increased PA activity in both cell types in a dose-dependent manner with ED50 of about 1 nM for both responses. Forskolin and isobutylmethylxanthine also stimulated PA activity and decreased PAI-1 protein and mRNA in both cell types. hPTH(1-34) did not show any consistent effect on tPA and uPA mRNA in calvarial osteoblasts, but a modest (two-fold) increase of both mRNAs was observed in UMR 106-01 cells treated with 25 nM hPTH(1-34). However, when protein synthesis was inhibited with 100 microM cycloheximide, the increase of tPA and uPA mRNA by hPTH(1-34) was enhanced in UMR 106-01 cells and became evident in calvarial osteoblasts. Fibrin autography also revealed that hPTH(1-34) increases tPA and uPA activity, especially after cycloheximide treatment in UMR 106-01 cells. These results strongly suggest that PTH increases PA activity predominantly by decreasing PAI-1 protein production through a cyclic adenosine monophosphate (cAMP)-dependent mechanism in rat osteoblasts. The reduction of PAI-1 protein by PTH results in enhanced action of both tPA and uPA, and would contribute to the specific roles of these PAs in bone.
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PMID:Plasminogen activator regulation in osteoblasts: parathyroid hormone inhibition of type-1 plasminogen activator inhibitor and its mRNA. 132 17

A variety of treatments, including acid, heparin, and proteases, are known to free insulin-like growth factors (IGFs) from their binding proteins (IGFBPs). However, the physiologically relevant mechanism regulating the interaction of IGFs and IGFBPs is unknown. We report here the ability of plasmin to dissociate IGFs from IGFBPs. In chromatographic experiments, plasmin completely dissociated complexes of [125I] IGF-I-BP and [125I]IGF-II-BP formed with purified decidual IGFBP (hIGFBP-1) or IGFBPs present in medium conditioned by human osteosarcoma MG-63 cells. Plasmin dissociation of IGF-BP complexes was dose dependent. Neither plasminogen nor plasminogen activators (PAs) alone affected dissociation; however, activation of plasminogen to plasmin by either urokinase PA or tissue-type PA resulted in the dissociation of IGF-BP complexes. Plasmin dissociated immunoreactive and bioactive IGF from IGFBP equivalent to approximately 70% and approximately 60% of the acid control value, respectively. In medium conditioned by MG-63 cells, dissociation of IGF-BP complexes was catalyzed by PAs secreted by MG-63 cells, principally urokinase PA. Limited plasmin degradation of IGF was suggested by chromatographic experiments involving [125I] IGF. Treatment of uncomplexed IGF-I with plasmin concentrations equivalent to those in chromatographic experiments did not result in a significant loss of bioactivity, although a 2-fold increase in the plasmin concentration resulted in a approximately 20% loss of activity. Similar plasmin treatment of equimolar concentrations of hIGFBP-1 resulted in a marked degradation of IGFBP, with loss of IGF-binding ability. In vitro experiments confirmed plasmin dissociation of bioactive IGF-I from hIGFBP-1. In MG-63 cells, IGFBPs can form an IGF reservoir in the pericellular space surrounding the cells by combining IGFs with IGF-BP to form complexes that are incapable of binding to the IGF receptors. The secretion of PAs by osteosarcoma cells and the availability of plasminogen in the extravascular tissues indicate the possibility of a regulatory system in osteosarcoma cells in which pericellular plasmin affects the availability of IGFs to their membrane receptors.
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PMID:Involvement of the plasmin system in dissociation of the insulin-like growth factor-binding protein complex. 137 48

Soluble chromium (VI) compounds either alone or in combination with 3-methylcholanthrene (MC) were used to transform non-tumorigenic osteoblast-like human osteosarcoma cells (HOS TE85). The Cr(VI) compounds were highly toxic to these cells with LC50 values in the range of approximately 0.5-1.0 microM. Continuous passaging of the treated cells resulted in sustained increase in anchorage-independent (AI) colony formation. Treatment with Cr(VI) and MC resulted in substantial increase in AI growth. At the XVth passage, a number of individual AI colonies were expanded in culture and used for further studies. The cells are refractory in appearance and grow as 'nests' rather than as monolayers. The cell lines have relatively high plating efficiency (PE) in soft agar and respond to promotional effect of phorbol-12-myristate-13-acetate by an increase in PE and in the size and number of AI colonies. While the isolated cells are not tumorigenic when tested in athymic nude mice, most of the lines possess higher levels of plasminogen activator (PA) activity, considered as one of the markers of transformation. This is also reflected in the increase in the steady state level of urokinase type PA mRNA. These results show that Cr(VI) compounds are capable of promoting human cells to an altered phenotype characteristic of a stage in the carcinogenesis cascade.
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PMID:Transformation of non-tumorigenic osteoblast-like human osteosarcoma cells by hexavalent chromates: alteration of morphology, induction of anchorage-independence and proteolytic function. 142 71

Transforming growth beta (TGF-beta) has been proposed to have a role in bone remodeling by affecting the differentiation and activity of osteoblasts and osteoclasts and by inhibiting the production of proteinases, such as plasminogen activators (PAs). Studies on PAs have largely been based on data from nonhuman and fetal cell lines, however. The purpose of this study was to investigate the effect of TGF-beta on the PA activity of normal human osteoblast-like cells and to compare this with its action on the human osteosarcoma cell line MG-63. The action of interleukin-1 beta (IL-1 beta) was also assessed because it has been shown to increase PA activity in other connective tissue cell types. Normal osteoblast-like cells had low to undetectable basal urokinase (uPA) and tissue plasminogen activator (tPA) activity, which was significantly stimulated by TGF-beta 1. This action was shown to be dependent on transcription and new protein synthesis. TGF-beta 2 had a similar action. IL-1 beta did not stimulate PA activity. In contrast, the MG-63 cell line had high basal tPA and uPA activities. TGF-beta 1 decreased basal PA activity, the effect being most marked for uPA activity. IL-1 beta stimulated uPA and tPA activity. TGF-beta 1 inhibited IL-1 beta-stimulated uPA activity, but the effect on tPA was more variable. This study has shown that TGF-beta has opposite effects on the PA activity of the two osteoblast-like cell types studied. Care must therefore be used before extrapolating data from one cell type to another.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of transforming growth factor beta on the plasminogen activator activity of normal human osteoblast-like cells and a human osteosarcoma cell line MG-63. 148 22

Glucocorticoids exert potent inhibitory effects on bone formation. We have previously shown that glucocorticoids suppress plasminogen activator (PA) activity in normal and malignant rat osteoblasts. To clarify the mechanism of this suppression, we investigated the effects of dexamethasone on PA inhibitor-1 (PAI-1), tissue-type PA (tPA), and urokinase-type PA (uPA) expression and also on PAI-1 protein and PA activity in both normal rat calvarial osteoblasts and a clonal osteogenic sarcoma cell line, UMR 106-01. Dexamethasone increased PAI-1 mRNA and protein in both cell types. The increase in PAI-1 protein and the decrease in PA activity were obtained over the same concentration range, with a half-maximally effective concentration of dexamethasone of about 10(-9) M. The increase in PAI-1 mRNA caused by dexamethasone was retained with cycloheximide treatment, but abolished with actinomycin-D. Dexamethasone had no effect on tPA or uPA mRNA in either cell type. The glucocorticoid antagonist RU 486 prevented the effects of dexamethasone on PA activity and PAI-1 protein. Dihydrotestosterone, progesterone, and 17 beta-estradiol did not influence PA activity or PAI-1 formation. Although tPA and uPA protein could not be measured, these results suggest that glucocorticoids suppress PA activity predominantly by increasing PAI-1 synthesis in rat osteoblasts. Suppression of PA activity through actions on PAI-1 formation by glucocorticoids could contribute to the mechanisms by which glucocorticoids inhibit bone formation.
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PMID:Glucocorticoid regulation of plasminogen activator inhibitor-1 messenger ribonucleic acid and protein in normal and malignant rat osteoblasts. 173 26

Transforming growth factor beta (TGF beta) treatment of rat osteoblast-rich calvarial cells or of the clonal osteogenic sarcoma cells, UMR 106-01, resulted in dose-dependent inhibition of plasminogen activator (PA) activity, and increased production of 3.2 kb mRNA and protein for PA inhibitor -1 (PAI-1). Although tissue-type PA (tPA) protein was not measured, TGF beta did not influence production of mRNA for tPA. Production of 2.3 kb mRNA for urokinase-type PA (uPA) was also increased by TGF beta in a dose-dependent manner. The effects of TGF beta on synthesis of mRNA for PAI-1 and uPA were maintained when protein synthesis was inhibited, and were abolished by inhibition of RNA synthesis. Although uPA had not been detected previously as a product of rat osteoblasts, treatment of lysates of osteoblast-like cells with plasmin yielded a band of PA activity on reverse fibrin autography, corresponding to a low Mr form of uPA. Untreated conditioned media from normal osteoblasts or UMR 106-01 cells contained no significant TGF beta activity, but activity could be detected in acidified medium. Treatment of conditioned media with plasmin resulted in activation of approximately 50% of the TGF beta detectable in acidified media. The results identify several effects of TGF beta on the PA-PA inhibitor system in osteoblasts. Net regulation of tPA activity through the stimulatory actions of several calciotropic hormones and the promotion of PAI-1 formation by TGF beta could determine the amount of osteoblast-derived TGF beta activated locally in bone. Stimulation of osteoblast production of mRNA for uPA could reflect effects on the synthesis of sc-uPA, a precursor for the active form of the enzyme.
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PMID:Transforming growth factor beta inhibits plasminogen activator (PA) activity and stimulates production of urokinase-type PA, PA inhibitor-1 mRNA, and protein in rat osteoblast-like cells. 183 80

The possible carcinogenicity of insoluble chromium (VI) compound, PbCrO4, in human cells has been tested using a nontumorigenic human osteosarcoma cell line (HOS, TE 85). Electron microscopic studies show that PbCrO4 is phagocytosed by HOS cells and accumulates within the vacuoles in the cytoplasm. A number of cell lines have been isolated following multiple treatment of HOS cells with PbCrO4. These cell lines are morphologically different from HOS cells, form anchorage-independent colonies in soft agar and form quickly regressing small tumor nodules in athymic nude mice. The cellular and secreted plasminogen activator (PA) levels of 5 cell lines isolated after PbCrO4 treatment are increased up to 8 fold and up to 10 fold respectively as compared to untreated HOS controls. SDS-PAGE analysis in the presence of copolymerized substrates is consistent with increase in 55 kDa urokinase-type PA (u-PA) and 68 kDa tissue-type PA (t-PA). These results show that PbCrO4 treatment leads to stable phenotypic changes indicative of the transformation of HOS cells.
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PMID:Induction of morphological transformation, anchorage-independent growth and plasminogen activators in non-tumorigenic human osteosarcoma cells by lead chromate. 188 37

Production of proteolytic enzymes by osteoblasts is considered to be important for the initiation of osteoclastic bone resorption. We examined the production of tissue-type (tPA) and urokinase-type plasminogen activator (uPA) activity by three types of osteoblast-like cells (normal rat osteoblasts, rat and human osteosarcoma cells) using a quantitative spectrophotometric assay and a qualitative gel overlay technique. All 3 types of cells released both types of PA-activity into the medium, but normal rat osteoblasts released uPA probably in an inactive form. Treatment with different concentrations of the bone resorbing factors bovine Parathyroid Hormone [1-84], synthetic human Parathyroid Hormone-Like Protein [1-34]. Prostaglandin E2, Interleukin-1 beta, Tumor Necrosis Factor alpha and 1,25-dihydroxyvitamin D3 increased in general the production of both PA's by all three cell types. However, there were differences in the relative potencies of these factors. In contrast, Transforming Growth Factor beta, which inhibits bone resorption, decreased PA-activity in osteoblast-like cells. In all three types of cells, under control as well as under stimulated conditions, a high molecular weight form of PA was demonstrated by the gel overlay technique, most likely a complex of tPA with the PA-inhibitor PAI-1. The uniform increase in production of PA's by osteoblast-like cells in response to bone resorbing factors and its decrease by TGF beta supports the notion that PA's are involved in bone resorption. The exact mechanism however, remains to be elucidated.
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PMID:Regulation of the production of plasminogen activators by bone resorption enhancing and inhibiting factors in three types of osteoblast-like cells. 193 92

Human tissue plasminogen activator (t-PA) was shown to bind specifically to human osteosarcoma cells (HOS), and human epidermoid carcinoma cells (A-431 cells). Crosslinking studies with DTSSP demonstrated high molecular weight complexes (130,000) between 125I-t-PA and cell membrane protein on human umbilical vein endothelial cells (HUVEC), HOS, and A-431 cells. A 48-65,000 molecular weight complex was demonstrated after crosslinking t-PA peptide (res. 7-20) to cells. Ligand blotting of cell lysates which had been passed over a t-PA affinity column revealed binding of t-PA to 54,000 and 95,000 molecular weight proteins. Several t-PA binding proteins were identified in immunopurified cell lysates, including tubulin beta chain, plasminogen activator inhibitor type 1 and single chain urokinase.
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PMID:Characterization of tissue plasminogen activator binding proteins isolated from endothelial cells and other cell types. 212 40


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