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

Certain metabolic properties of hormonally responsive osteogenic sarcoma cells derived from a transplantable rat tumor have been compared with those of related normal rat bone cells. All studies were carried out on cells grown in monolayer culture. Normal rat bone cells derived by repeated collagenase/trypsin digestion of newborn rat calvaria. Bone cells selected for comparison were thought to be osteoblast-like, as judged by enrichment of alkaline phosphatase and adenylate cyclase responsiveness to parathyroid hormone and prostaglandin E2. The adenylate cyclases of the two cell strains were similarly stimulated by a range of prostanoids and their metabolites and analogs. Morphology showed the two cell strains to be similar; the only obvious difference was a multilayering of cells in the sarcoma cultures, while the normal cultures showed abundant extracellular fibril formation which was not seen in the tumor cells. Investigation of the cAMP-dependent protein kinase isoenzymes showed the presence of two forms in both cell types, one eluting at a low salt concentration and the other at a high salt concentration. There was approximately twice the amount of the first isoenzyme compared to the second isoenzyme. The results indicate the usefulness of the two cell strains to elucidate further the molecular mechanisms of action of parathyroid hormone and prostaglandins.
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PMID:Functional properties of hormonally responsive cultured normal and malignant rat osteoblastic cells. 693 60

Many clinical studies have been conducted on the role of high-dose methotrexate (MTX) in human osteosarcoma, but information about the in vitro effect of MTX on human osteosarcoma cells is lacking. In this paper, the effect of MTX on tumor cells derived from seven patients with osteosarcoma has been studied in an attempt to correlate clinical and in vitro sensitivity to the drug. Isolation of the cells from the primary tumors (four patients) or metastasis (three patients) was carried out with a collagenase treatment followed by purification through a density gradient. The osteosarcoma cells were identified by electron microscopy and histochemical reactions. The cellular sensitivity to MTX was measured by the inhibitory effect of MTX on [3H]deoxyuridine incorporation into DNA. This incorporation ws 50% inhibited in primary tumors at concentrations from 3 X 10(-7) to 3 X 10(-6) M. The metastatic cells isolated from patients that were clinically resistant to high-dose MTX had a 50% inhibition ranging from 1.5 X 10(-7) to 4 X 10(-5) M. Human stimulated lymphocytes, Sarcoma 180 cells, and Ehrlich ascitic mouse cells had a 50% inhibition of about 1.5 X 10(-7) M. When [3H]thymidine incorporation into DNA of human osteosarcoma cells was studied, it was observed that MTX increased its incorporation up to 4-fold. This increase was stable for at lest 6 hr and was only slightly enhanced by the addition of hypoxanthine. The stimulation by MTX of [3H]thymidine incorporation into DNA in stimulated lymphocytes and Ehrlich cells is much smaller, between 40 and 60%. A hypothesis to explain these results is that osteosarcoma cells build their deoxythymidine monophosphate pool largely through the de novo pathway, the salvage pathway being less important. It is suggested that the importance of the de novo pathway for deoxythymidine monophosphate synthesis is a biochemical characteristic of the osteosarcoma cells which could be related to the initial sensitivity of this tumor to MTX and that an activation of the salvage pathway could constitute an additional mechanism of resistance to this drug.
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PMID:Isolation of tumor cells from patients with osteosarcoma and analysis of their sensitivity to methotrexate. 694 15

Plasmin-mediated extracellular proteolysis has been implicated in the degradation of bone in normal and pathological conditions. Normal and malignant osteoblasts can produce both tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). We have used the osteosarcoma cell line MG63 to address the question of whether the enhanced bone turnover in osteosarcomas is mediated by t-PA or by u-PAA and to study the effect of the cytokine interleukin-1 alpha (IL-1 alpha), known to influence bone degradation, on the plasminogen activator production and extracellular matrix degradation in malignant osteoblastic cells. Furthermore, the effect of IL-1 alpha on the synthesis of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) was analyzed. u-PA production by MG63 was high (approximately 180 ng/10(6) cells/24 h). Also t-PA and PAI-1 production was observed. u-PA production was rapidly increased in MG63 by IL-1 alpha (10 ng/ml), whereas an effect on t-PA production was only found after a prolonged incubation and hardly any effect of IL-1 alpha on PAI-1 production was observed. mRNA analysis revealed similar effects. u-PA receptor (u-PAR) mRNA was detectable in MG63 cells and could be increased by IL-1 alpha after 24 h. In MG63, u-PA-mediated extracellular matrix degradation was detectable, and IL-1 alpha increased the u-PA-mediated matrix degradation (approximately 2-fold). Under control conditions in MG63, only MMP-2, TIMP-1, and TIMP-2 mRNA could be observed. After the addition of IL-1 alpha, a very rapid increase in MMP-1 and MMP-3 mRNA could be observed as well as a moderate increase in TIMP-1 mRNA. The presence of MMP-2 was demonstrated by gelatin zymography. These results show that IL-1 alpha can stimulate u-PA production and can regulate extracellular proteolytic activity mainly via u-PA induction in the MG63 osteosarcoma cell line. Furthermore, IL-1 alpha has a strong stimulating effect on the production of MMP-1 and MMP-3. These findings suggest that u-PA and possibly MMP-1 and MMP-3 play an important role in the process of bone turnover in osteosarcomas.
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PMID:Regulation of plasminogen activation, matrix metalloproteinases and urokinase-type plasminogen activator-mediated extracellular matrix degradation in human osteosarcoma cell line MG63 by interleukin-1 alpha. 750 10

We recently showed that osteogenic protein-1(OP-1), a bone morphogenetic protein member of TGF-beta superfamily, induces endochondral bone formation in vivo, and stimulates growth and differentiation of osteoblasts in rat calvarial-derived cell cultures. In the present study, we examined the effect of OP-1 on cell growth and expression of markers that are characteristic of osteoblast phenotype using the clonal rat osteosarcoma cells (ROS 17/2.8). A comparison of OP-1 and TGF-beta 1 effects on cell growth showed that, both OP-1 and TGF-beta 1 inhibited DNA synthesis up to 90 percent and 60 percent of the controls at concentrations of 10 ng/ml and 1 ng/ml, respectively, in serum-free medium. In the presence of 5% serum, TGF-beta 1 did not have any significant inhibitory effects while 40 ng OP-1/ml inhibited the DNA synthesis up to 80% of the controls. Examination of collagen synthesis showed that 40 ng OP-1/ml increased the expression of type I collagen mRNA, and thus increased collagen synthesis (4-fold), as examined by collagenase-digestible protein. Evaluation of markers that are characteristic of the osteoblast phenotype demonstrated that OP-1 stimulated cAMP production in response to PTH (10-fold at 200 ng/ml), alkaline phosphatase specific activity (ALPase) (4-fold at 80 ng/ml), and osteocalcin (OC) synthesis (4.5-fold at 40 ng/ml). Northern blot analysis revealed that OP-1 increased mRNA expression for both ALPase and OC in a dose-dependent manner. These data collectively demonstrate that OP-1 suppresses cell proliferation and stimulates the expression of markers characteristic of osteoblast phenotype in rat clonal osteoblastic osteosarcoma cells (ROS 17/2.8).
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PMID:Osteogenic protein-1 (BMP-7) inhibits cell proliferation and stimulates the expression of markers characteristic of osteoblast phenotype in rat osteosarcoma (17/2.8) cells. 773 48

The triterpenes, alpha-amyrin (AA) and its palmitate (AAP) and linoleate esters (AAL), were tested on models of inflammatory and destructive arthritic processes and their effects were compared with the clinical antiarthritic drugs indomethacin (IN) and methotrexate (MTX). The triterpenes had no effect on the prostaglandin phase of carrageenin pedal edema in rats, which was reduced 28% by 100 microM IN. AAL caused a considerable reduction in the synthesis by human neutrophils of 5-lipoxygenase products--5-HETE (IC50 = 70 microM), LTB4, (62 microM), isomer I (30 microM) and isomer II (24 microM). Rat osteosarcoma cell growth was inhibited by all triterpenes with IC50's (microM) of < 10 (AAP), 14 (AA) and 27 (AAL) and were more effective than IN (35). MTX caused 100% inhibition at a concentration of 10 microM compared with 64% inhibition by AAP. Tadpole collagenase digestion of type I (bone) native collagen was completely inhibited by all the triterpenes as well as IN and MTX at 100 microM. The results indicate that the principal point of antiarthritic intervention by amyrin triterpenes lies in their local inhibition of joint destruction.
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PMID:Antiarthritic mechanisms of amyrin triterpenes. 795 94

To determine how progestins increase bone formation in vivo, the effects of the synthetic progestin norethindrone (NET), on aspects of bone formation in vitro were determined. NET at picomolar concentrations in vitro stimulated the proliferation of human TE85 osteosarcoma cells as assessed by the increase in [3H]thymidine incorporation into DNA and in cell number and also stimulated the release of osteocalcin in both the presence and absence of 10 nM 1,25-(OH)2D3. NET increased cellular alkaline phosphatase specific activity (an index of osteoblastic differentiation), but at much higher concentrations, that is, nanomolar. These findings suggest that low concentrations of NET act directly on human TE85 osteosarcoma cells to stimulate their proliferation, differentiation, and cell activity. Furthermore, mitogenic doses of NET stimulated bone collagen synthesis both in a chicken calvarial organ culture assay (assessed by the incorporation and hydroxylation of [3H]proline) and in a human TE85 osteosarcoma cell culture assay (determined by the incorporation of [3H]proline into collagenase-digestible proteins). In contrast, NET at 10(-6)-10(-12) M had no apparent effect on the rate of basal or PTH-stimulated release of 45Ca from prelabeled mouse calvariae in vitro. In summary, this study has demonstrated for the first time that picomolar NET acted directly on human TE85 osteosarcoma cells to increase (1) cell proliferation and differentiation, (2) osteoblastic activity (i.e., osteocalcin synthesis), and (3) bone collagen synthesis in vitro. The same doses of NET in vitro did not reduce the bone resorption rate under our assay conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Picomolar norethindrone in vitro stimulates the cell proliferation and activity of a human osteosarcoma cell line and increases bone collagen synthesis without an effect on bone resorption. 805 99

The proto-oncogene transcription factors Fos and Jun form a heterodimeric complex that binds to DNA and regulates expression of specific target genes. Continuous expression of c-fos causes transformation of cultured fibroblasts and induces osteogenic sarcoma in mice. To investigate the molecular basis of fos-mediated oncogenesis, we developed a conditional cell transformation system in which Fos expression was regulated by isopropyl-beta-D-thiogalactopyranoside (IPTG). Synthesis or repression of Fos in L1-3c-fos cells occurred rapidly, within 30 min, after the removal or addition of IPTG to the culture medium. However, there was a significant delay between the induction of Fos expression and the appearance of morphological transformation. No effect was observed after 12 h of Fos expression, partial transformation was detected after 24 h, and full transformation required approximately 3 days of continuous Fos expression. Similarly, the transformed cell morphology persisted for at least 2 days after repression of Fos, and a normal phenotype was observed only after 3 days. Fos-Jun complexes, capable of binding to AP-1 sequences, were present continuously during the delay in morphological transformation. Furthermore, increased expression of several candidate Fos target genes, including those encoding Fra-1, transin (stromelysin), collagenase, and ornithine decarboxylase, was detected shortly after Fos induction. The induction of morphological transformation was not dependent on the cell cycle, as it occurred in both cycling and noncycling cells. Thus, the Fos-Jun complexes present before L1-3c-fos cells become fully transformed are transcriptionally active. These complexes disappeared, and the Fos target genes were repressed at least 2 days prior to reversion. Our results suggest that cell transformation by Fos requires increased expression of a target gene(s) with a long-lived product(s) that must reach a critical level.
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PMID:Cell transformation by c-fos requires an extended period of expression and is independent of the cell cycle. 819 66

To more clearly define the expression of metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) within the human osteoblast (hOB) lineage, normal hOB and human osteogenic sarcoma cells possessing various levels of alkaline phosphatase (a marker of commitment to the osteoblast lineage) were treated with bone-resorbing agents to determine their effect on the production of interstitial collagenase, stromelysin, 72-kilodalton (kDa) gelatinase, 92-kDa gelatinase, TIMP-1, and TIMP-2. The results revealed that 1) normal hOB release copious amounts of 72-kDa gelatinase, TIMP-1, and TIMP-2; 2) hOB production of 72-kDa gelatinase and TIMP-2 is not regulated by agents that promote bone resorption (e.g. phorbol-12-myristate 13-acetate, recombinant human interleukin-1 beta, tumor necrosis factor-alpha, PTH, and vitamin D3); 3) normal hOB fail to secrete collagenase, stromelysin, or 92-kDa gelatinase when cultured on plastic or a type I collagen substratum, even in response to bone-resorptive agents or mononuclear cell-conditioned medium; 4) in contrast, certain of the osteogenic sarcoma cell populations produce collagenase, stromelysin, and 92-kDa gelatinase, especially when exposed to bone-resorbing stimuli; 5) in general, the capacity for metalloenzyme production by osteogenic sarcoma cell lines varies inversely with their alkaline phosphatase expression; and 6) the most committed (highest alkaline phosphatase) osteogenic sarcoma cell line, SAOS-2, precisely mimics the metalloproteinase profile of normal hOB. The results suggest that the expression of most metalloproteinases is under strict repression within the differentiated normal hOB, and cellular development is associated with diminished capacity to elaborate such enzymes.
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PMID:Expression of metalloproteinases and tissue inhibitors of metalloproteinases in human osteoblast-like cells: differentiation is associated with repression of metalloproteinase biosynthesis. 827 36

Transgenic mice overexpressing the c-fos proto-oncogene in bone develop osteosarcomas, whereas mice overexpressing c-Jun are normal. In this study, we investigated whether Fos and Jun would cooperate in vivo and whether the threshold levels of Fos are important in osteosarcoma formation. Fos-Jun double-transgenic mice develop osteosarcomas at a higher frequency than single-Fos transgenic mice with no differences in the time of onset of tumor formation. Histological and histochemical analyses indicated that Fos-Jun tumors contained greater quantities of neoplastic bone, were more remodeled, and contained a greater number of multinucleated osteoclast-like cells than tumors isolated from age-matched, single transgenic littermates. In contrast, overexpression of Fos in knockout mice that lack endogenous Fos resulted in a decrease in the number of tumor-bearing mice; osteosarcomas were almost absent in c-fos -/- mice, whereas tumor incidence was reduced to approximately 50% in c-fos +/- mice. Cell lines isolated from Fos-Jun transgenic tumors expressed high levels of both transgenes but significantly lower levels of the jun-related gene junB compared with cells expressing only a c-fos transgene. Osteoblastic marker genes were expressed at varying levels in different cell lines, but expression of interstitial collagenase (matrix metalloproteinase-1) was enhanced in cells derived from Fos-Jun tumors. These studies demonstrate that coexpression of a c-jun transgene can enhance Fos-induced oncogenesis in vivo and suggest that a critical level of Fos is necessary for osteosarcoma development.
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PMID:c-fos-induced osteosarcoma formation in transgenic mice: cooperativity with c-jun and the role of endogenous c-fos. 852 21

The expression of parathyroid hormone-related protein (PTHrP) was studied in a range of cell cultures representative of the osteoblast lineage and in rat calvarial sections. Primary newborn rat calvarial cells, a rat preosteoblastic cell line (UMR 201), a mouse stromal cell line (ST 2), a mouse calvaria-derived osteoblastic cell line (KS 4), and rat osteosarcoma cell lines (UMR 106-01 and -06), all expressed PTHrP when examined by reverse transcription polymerase chain reaction (RT-PCR). Using a radioimmunoassay we also demonstrated PTHrP in the conditioned medium of the cultured cells, with the exception of UMR 106-01 and -06 cells. Treatment of UMR 201 cells with all-trans-retinoic acid which induces them to acquire a more differentiated phenotype, also led to a time-dependent decrease in PTHrP mRNA levels as determined by RT-PCR, Northern blot analysis, and in situ hybridization. Decreased PTHrP levels in the conditioned medium of the treated cells was also observed. These results suggested that PTHrP production might be greater in less mature osteoblasts. Examination of the populations obtained from newborn rat calvariae by sequential collagenase digestion revealed that the early digests exhibited low ALP activity, low expression of PTH/PTHrP receptor mRNA, and no adenylate cyclase response to PTHrP(1-34). These populations showed the highest level of mRNA and production of PTHrP. Cells from later digests, the "osteoblast-rich" populations, had reduced PTHrP expression. Immunohistochemistry and in situ hybridization in sections of newborn rat calvariae showed PTHrP expression in cuboidal osteoblasts located adjacent to bone and in spindle-shaped cells in the periosteal region. It is concluded that PTHrP is produced by cells of the osteoblast lineage, supporting the hypothesis that PTHrP may function physiologically as a paracrine factor in bone.
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PMID:Expression of parathyroid hormone-related protein in cells of osteoblast lineage. 855 80


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