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)

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

Cell-matrix interactions and intergrin-type cell adhesion receptors are involved in the regulation of tumor cell invasion and metastasis. We have analyzed the expression of matrix proteins and their cellular receptors in human osteosarcoma cells (HOS) and in their virally (KHOS-NP) and chemically (HOS-MNNG) transformed tumorigenic subclones. Transformation decreased dramatically the cellular mRNA levels of alpha 1(I) collagen. Concomitantly with down-regulation of collagen mRNA levels the synthesis of the collagen receptor, alpha 2 beta 1 integrin, was induced. No alpha 2 integrin mRNA was found in HOS cells, suggesting that its expression was regulated most probably at the transcriptional level. 5-Azacytidine alone or combined with alpha 2 integrin-stimulating cytokines, transforming growth factor-beta 1, and interleukin-1 beta, did not turn on the alpha 2 integrin gene. In chemically transformed cells, however, alpha 2 integrin expression could be regulated by cytokines. Thus, we suggest that HOS cells have a strong element, probably other than cell culture-generated de novo promoter methylation, suppressing alpha 2 integrin expression and that this factor is lost in both chemical and viral transformation. Furthermore, the mechanism used by cytokines and malignant transformation to increase alpha 2 integrin expression seems not to be identical. Other transformation-related changes in beta 1 integrins were (i) reduction of the intracellular pool of precursor beta 1 (in HOS-MNNG cells), leading to faster maturation rate of beta 1 subunit and slower maturation rate of alpha subunits, and (ii) decreased electrophoretic mobility of both alpha and beta 1 subunits. At the cellular level both chemical and viral transformation increased cell adhesion to type I collagen.
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PMID:Suppressed collagen gene expression and induction of alpha 2 beta 1 integrin-type collagen receptor in tumorigenic derivatives of human osteogenic sarcoma (HOS) cell line. 828 90

Gallium nitrate (GN) is an inhibitor of bone resorption and thereby may result in a change in coupled bone formation. In the present investigation the effects of GN on bone formation were studied in the rat osteosarcoma (ROS) 17/2.8 cell line and normal diploid rat osteoblasts (ROB) in vitro and the femur of rats treated in vivo, measuring mRNA levels for two osteoblast parameters, type I collagen, a marker of matrix formation, and osteocalcin, a bone specific protein and also histone H4, a marker of cell proliferation. GN, at 50 microM for 3 h, increased type I collagen mRNA levels by 132% in ROS 17/2.8 cells and by 122% in proliferating ROB cells. Osteocalcin (OC) mRNA levels were decreased by 61% in ROS 17/2.8 cells and by 97% in differentiated ROB cells. These changes occurred in the absence of any effects on cell proliferation. Seventy-day-old female rats were then treated with GN, 0.5 mg/kg/day, for 3 weeks. As previously reported, GN decreased serum calcium levels, but had no effect on lumbar or femoral bone density. In contrast to the in vitro effects, GN had no effect on type I collagen steady-state mRNA levels in the femur; however, it decreased OC steady-state mRNA levels in the femur by 58%. These results suggest that GN has similar in vitro effects in transformed and normal osteoblasts, while the collagen-stimulatory effects observed in vitro cannot be extrapolated to in vivo models. The consistent inhibition of osteocalcin in vitro and in vivo suggests a more specific target for GN that may relate to its effects in inhibiting bone resorption in normal rats.
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PMID:Effect of gallium nitrate in vitro and in normal rats. 836 44

The authors studied effect of chemotherapy on osteosarcoma by collagen analysis. As a result of this case study we propose the induction of osteosarcoma differentiation by chemotherapy. Treatment of a conventional osteosarcoma with two intra-arterial infusions of cisplatin and the T-12 protocol of Rosen resulted in sclerotic changes and good margination accompanied by the disappearance of the soft-tissue component from the X-rays. More than 90% tumour destruction was histologically demonstrated; tumour bone and osteoid increased after the chemotherapy, and the viable area of the tumour resembled an osteoblastoma. Before the chemotherapy, immunolocalization determined collagen types I and V to be diffusely present in the bone and osteoid. After the chemotherapy, the antibody to type I collagen was diffusely present, but the antibody to type V collagen occurred only on the surface of the increased bone and osteoid as in normal bone. When osteosarcoma cells were treated in vitro with methotrexate or cisplatin, collagen production increased significantly. It is thus believed that tumour cells were directly stimulated with these chemotherapeutic agents to produce collagen. The findings suggested that some anticancer agents might not only be cytotoxic to but also differentiate osteosarcoma cells.
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PMID:Chemotherapeutic effect on osteosarcoma on basis of collagen analysis: a proposal of the induction of osteosarcoma differentiation. 840 82

Two sets of clonal cell populations differing in the expression of osteoblastic traits, the rat osteosarcoma cell lines ROS 17/2.8 and ROS 25/1 and the immortalized fetal rat calvarial cell lines RCT-1 and RCT-3, were compared for their ability to attach to a series of extracellular matrix (ECM) constituents in vitro. Both osteoblastic (ROS 17/2.8, RCT-3) and nonosteoblastic (ROS 25/1, RCT-1) cell lines attached in a time- and concentration-dependent manner to plates coated with fibronectin (FN), osteopontin (OP), type I collagen (Col I), type IV collagen (Col IV), and laminin (LN) but only weakly to osteocalcin (OC) and thrombospondin (TSP). In both systems, the osteoblastic and nonosteoblastic clones attached identically to FN. Both ROS 17/2.8 and ROS 25/1 attached to similar molar amounts of substrate with the same preference order: FN > LN > Col I > or = Col IV. Maximal ROS 17/2.8 attachment to OP was > or = Col I but required approximately 2.5 times more substrate. ROS 25/1 attached less effectively than ROS 17/2.8 to most non-FN substrates. RCT-3 cells attached similarly to ROS 17/2.8 except that the preference order for Col I and LN was reversed and attachment to OP was lower than for ROS 17/2.8 RCT-1 cells attached best to Col I rather than FN, and equaled or surpassed RCT-3 in attachment to other non-FN substrates. Thus in these experimental systems, cells expressing an osteoblast-like phenotype exhibited generally similar ECM attachment properties. Their nonosteoblastic counterparts recognized the same spectrum of ECM constituents but differed from the osteoblastic cells and from each other in the effectiveness of their attachment to substrates other than FN.
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PMID:Attachment to extracellular matrix molecules by cells differing in the expression of osteoblastic traits. 845 84

The effect of recombinant Pasteurella multocida toxin (PMT) on primary cultures of embryonic chick bone-derived osteoblastic cells was investigated. It was found that PMT was a potent mitogen for primary derived chicken osteoblasts. The toxin stimulated DNA synthesis and cell proliferation in quiescent osteoblasts at the first passage and accelerated cell growth in subconfluent cultures. Cell viability was not affected by PMT, even at relatively high concentrations. Osteoblast numbers increased in a dose-dependent manner in response to PMT. Intracellular inositol phosphates were elevated in response to PMT, but no elevation in cyclic AMP (cAMP) levels was evident. Indeed, PMT inhibited cAMP elevation in osteoblasts in response to cholera toxin at a stage before other PMT-mediated events take place. In addition to increased cell turnover, PMT down-regulated the expression of several markers of osteoblast differentiation. Both alkaline phosphatase and type I collagen were reduced, but osteonectin was not affected. The in vitro deposition of mineral in cultures of primary osteoblasts and osteoblast-like osteosarcoma cells was also inhibited by the presence of PMT. This suggests that PMT interferes with differentiation at a preosteoblastic stage.
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PMID:Pasteurella multocida toxin is a mitogen for bone cells in primary culture. 864 7

We have previously shown that the response of osteoblasts to parathyroid hormone (PTH) can be influenced at the receptor level by growth on the physiological substrate, type I collagen, or by treatment with retinoic acid. We have also shown differential expression of genes when cells of the osteoblast lineage are grown on type I collagen. The aim of this study was therefore to examine the effect of retinoic acid and growth on type I collagen on PTH/PTH-related protein (PTHrP) receptor mRNA expression in the osteosarcoma osteoblast-like cell line UMR 106-06. PTH/PTHrP receptor mRNA levels, as assessed by Northern blot, of cells grown on collagen were increased up to 2-fold compared with cells on plastic and in a concentration-dependent manner with respect to collagen. An increase was seen as early as 6 h and was maintained over a 24 h period. This was not due to increased mRNA stability. Retinoic acid decreased the level of receptor mRNA on both plastic and collagen at each time but did not alter mRNA stability. For all treatments PTH/PTHrP receptor mRNA abundance, relative to glyceraldehyde-3-phosphate dehydrogenase, increased steadily over 24 h after subculture of cells. In contrast, PTHrP mRNA levels were reduced in cells on collagen, compared with plastic. PTH-stimulated cAMP levels of cells grown on collagen were increased compared with plastic at 24 h, but not earlier. Consistent with the mRNA data, retinoic acid decreased the amplitude of cAMP responses in cells on plastic and collagen. There was no evidence for changes in adenylate cyclase per se, since forskolin-induced cAMP levels did not change with either treatment. This study shows that known modulators of osteoblast maturation also affect signal transduction in these cells by regulating gene expression of the PTH/PTHrP receptor as well as the PTHrP ligand.
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PMID:A type I collagen substrate increases PTH/PTHrP receptor mRNA expression and suppresses PTHrP mRNA expression in UMR106-06 osteoblast-like cells. 886 96

A cell culture inside a three-dimensional gel of fibrillar collagen is an experimental model used to study the response of cells to the extracellular matrix. Many cell types induce the contraction of gel and simultaneously decrease their production of type I collagen, whereas the expression of interstitial collagenase (matrix metalloproteinase-1; MMP-1) is enhanced. We have previously shown that in osteogenic cells the collagen receptor alpha2beta1 integrin is a positive regulator of MMP-1 and that the number of alpha2beta1 integrins on the cell surface also regulates the magnitude of contraction. However, the downregulation of collagen mRNA levels is not initiated by alpha2beta1 integrin. Here, we have studied in human KHOS-240 and MG-63 osteosarcoma cells and in human skin fibroblasts the effects of tyrosine kinase inhibitors on collagen gel contraction and on the regulation of MMP-1 and collagen alpha1(I) genes by extracellular collagen. The induction of MMP-1 could be inhibited by all tyrosine kinase inhibitors tested with the exception of genistein. None of them could prevent the downregulation of collagen expression. Thus, the collagen-induced alterations in the expression of MMP-1 and collagen alpha1(I) seem to be dependent on distinct signal transduction pathways. Many of the inhibitors, including genistein, could prevent the contraction of collagen gels. The effect was not related to their ability to inhibit cell growth, because an inhibitor specific for DNA synthesis and cell division did not have the same effect. Thus, we suggest that the process of collagen gel contraction requires protein-tyrosine phosphorylation and that the ability of cells to contract collagen gels is not related to the induction of MMP-1 or to the level of collagen alpha1(I) expression. Finally, we propose that the tyrosine kinase inhibitors might be considered as candidate molecules in the treatment of pathological scar contraction.
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PMID:Integrin alpha2beta1-dependent contraction of floating collagen gels and induction of collagenase are inhibited by tyrosine kinase inhibitors. 889 67

The nuclear matrix mediates the 3-dimensional organization of DNA and supports DNA replication and its transcription. We hypothesize that the osteoblast nuclear matrix contributes to the transcriptional control of type I collagen (COL1A1) expression. Cis-regulatory elements of the rat COL1A1 promoter that control osteoblast expression in vivo are between -2.3 and -1.67 kilobase pairs (kb) but lie within -3.5 and -2.3 kb in cultured bone cells. This may result from differences in cell architecture between osteoblasts in tissue and those in vitro. Our aim was to identify osteoblast nuclear matrix proteins (NMPs) that associated with sequence-specificity to the COL1A1 promoter. We used osteoblasts from the rat metaphyseal femur and the rat osteosarcoma cells, ROS 17/2.8. Nuclear matrix and soluble nuclear proteins were obtained as separate subfractions. Gel mobility shift analysis, using fragments of the COL1A1 promoter, was used to identify DNA-binding proteins in the nuclear subfractions. A NMP-DNA interaction, NMP3, was observed between -2149 and -2106 nucleotide in both osteoblasts and osteosarcoma cells. NMP4 was detected between -3518 to -3406 nucleotide. Therefore, osteoblast NMPs recognize sequences in regulatory regions of the COL1A1 promoter and may link cell structure and the transcriptional regulation of this protein.
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PMID:Rat osteoblast and osteosarcoma nuclear matrix proteins bind with sequence specificity to the rat type I collagen promoter. 897 38

Human osteosarcomas are aggressive bone tumors. Here we propose that their progression requires altered cell interaction with extracellular matrix. Since type I collagen is the main matrix molecule found in bone and thus obligated to interact with tumor cells, we analyzed the expression and function of different integrin-type collagen receptors in tumor cell-collagen interaction by using eight human osteogenic sarcoma (HOS) cell lines. Virally (Kirsten sarcoma virus) transformed derivatives of HOS cells (KHOS-NP) and chemically [N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)] transformed tumorigenic subclones of human osteogenic sarcoma cells (HOS-MNNG) expressed alpha 2 beta 1 integrin in remarkably larger amounts than the six other nontumorigenic cell lines (HOS, MG-63, Saos-2, KHOS-240, KHOS-312, and G292). Concomitantly, Mg(2+)-dependent adhesion of tumorigenic cells to type I collagen was increased. We also show that the migration of tumorigenic cells on and invasion through type I collagen is faster than that of HOS cells. HOS cells forced to express alpha 2 integrin by cDNA transfections showed increased Mg(2+)-dependent cell adhesion to type I collagen and also accelerated migration and invasion rate, indicating that the overexpression of alpha 2 beta 1 integrin in tumorigenic cells alone explains the altered cell-collagen interaction. Finally, HOS cells forced to express alpha 2 integrin subunit did not grow s.c. in athymic mice, suggesting that overexpression of alpha 2 integrin is not efficient to make these cells tumorigenic.
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PMID:Integrin alpha 2 beta 1 in tumorigenic human osteosarcoma cell lines regulates cell adhesion, migration, and invasion by interaction with type I collagen. 905 85


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