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)

Human osteosarcoma and mammary carcinoma cells were cultured separately in a medium supplemented with fetal calf serum, until they were confluent. The medium was then replaced by serum-free medium supplemented with heparin. Both cell cultures secreted collagenase, and this activity was inhibited by a cartilage-derived protein of low molecular weight. Since cartilage is rarely invaded by neoplasms, the presence of this inhibitor may play an important role in the regulation of tumor invasion.
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PMID:Tumor cell collagenase and its inhibition by a cartilage-derived protease inhibitor. 19 81

Histophysiology, ultrastructure, chemical analyses of transplants and implants of Dunn and Ridgway mouse osteosarcomas demonstrate that tumorigenesis is a manifestation of deranged morphogenesis in developing mesenchymal cell populations. The end product of development is defective, incompletely calcified, disorganized bone without any inclusions of bone marrow tissue. When Dunn osteosarcoma is freeze-dried and then implanted, the tumor is resorbed and replaced by deposits of normal cartilage, bone, and bone marrow. Freeze-dried Ridgway osteosarcoma is replaced only by a fibrous connective tissue scar. Disaggregated Dunn tumor osteoblasts synthesize a trypsin-labile collagenase-resistant cell surface localized bone morphogen. Tumor matrix stroma, prepared by sequential chemical extraction of soluble non-collagenous proteins also contains significant quantities of the same bone morphogen. Tumor tissue pulverized to particle size as small as 44 micrometer3 transmitted bone morphogen more rapidly than intact tumor tissue. The total tumor cell and stroma mediated bone morphogen produces three times more normal bone than normal cortical bone matrix. Our working hypothesis is that a normal bone morphogenetic polypeptide (BMP) is synthesized by Dunn osteosarcoma cells and retained by the tumor matrix stroma. Neither the mechanism of transmission nor the mesenchymal cell receptor sites of BMP are known.
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PMID:An osteosarcoma cell and matrix retained morphogen for normal bone formation. 27 29

Adenylate cyclase activity in particulate fractions from a transplantable rat osteogenic sarcoma was stimulated in a dose-dependent manner by prostaglandins E1 and E2 (PGE1 and PGE2) and parathyroid hormone (PTH). Prostaglandin F2alpha was active at a high concentration (3 x 10(-4) mol/l). Pretreatment of membranes with collagenase plus hyaluronidase reduced the magnitude of the PTH effect but did not affect the size of the PGE1 effect. Guanosine 5'-triphosphate and its synthetic analogue 5'-guanylylimidodiphosphate (Gpp(NH)p) activated adenylate cyclase in particulate preparations from the osteogenic sarcoma. The latter agent produced much larger effects, although the concentrations required for half-maximal enzyme activation were the same for both agonists (approximately 2 x 10(-6) mol/l). The effects of PTH and Gpp(NH)p were supra-additive at some concentrations of hormone. The effects of PGE1 and Gpp(NH)p were supra-additive at all hormone concentrations tested. Pre-incubation of membrane particles for 6 min with PTH produced an enzyme activation which was not reversed by dilution through washing; pre-incubation with PGE1 did not produce this effect. The response of membrane adenylate cyclase to Gpp(NH)p (10(-4) mol/l) was 75% greater in preparations pre-incubated with PTH than in membranes pre-incubated in buffer alone or in buffer containing PGE1. The basal rate of cyclic AMP production in the adenylate cyclase assay system decreased over a 35 min incubation period. This decrease was prevented by addition of PTH or PGE1. Addition of NaF or Gpp(NH)p produced a steady increase in the rate of production of cyclic AMP with time. Membrane preparations did not reduce the biological activity of PTH and did not degrade 125I-labelled PTH. The results demonstrate that the PTH- and PGE-responsive adenylate cyclases of the osteogenic sarcoma have distinctly different properties and that particulate preparations of the tumour do not metabolize PTH.
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PMID:Membranes from a transplantable osteogenic sarcoma responsive to parathyroid hormone and prostaglandins: regulation of adenylate cyclase and of hormone metabolism. 27 36

The present study was designed to further understand the role of PTH on the secretion of the neutral metalloproteinases, collagenase and gelatinase, from the rat osteosarcoma clonal cell line, ROS 17/2.8. Semiconfluent cells were treated with bovine parathyroid hormone, b-PTH-(1-34) at 100 nM-0.01 nM for 24-96 hours and pooled, concentrated media were analyzed by functional assay for collagenase (3H-methyl collagen) and gelatinase (3H-methyl gelatin). Collagenase activity significantly decreased (P less than 0.01) in the PTH conditioned media in a dose-dependent manner before (98-64%) and after (91-39%) reduction and alkylation. SDS-PAGE and fluorography apparently showed the most degradation to alpha A chains in collagen with controls, whereas this substrate remained intact with PTH (100 nM). PTH (100 nM) media also showed neutral gelatinase activity approximately 2% compared to control before and after reduction and alkylation (P less than 0.01). Significant amounts of an inhibitor to collagenase and gelatinase might have been secreted at 1 nM and 0.01 nM PTH, since collagenase and gelatinase activities were greater after reduction and alkylation. Reduction and alkylation likely destroyed these significant amounts of inhibitor. Polymorphonuclear leukocyte collagenase activity was also inhibited 80% by PTH conditioned media, but not by control. However, upon reduction and alkylation which destroyed inhibitor, the PTH treated media showed only a 14% inhibition against polymorphonuclear leukocyte collagenase (P less than 0.01). PTH appeared to downregulate neutral metalloproteinase activities through its effects on an inhibitor. This downregulation may represent a specific phenotypic response to PTH in ROS 17/2.8 cells.
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PMID:Parathyroid hormone regulation of matrix degrading enzymes in rat osteoblastic osteosarcoma 17/2.8 cells. 132 16

Regulation of the synthesis of collagenase was investigated in the osteoblastic cell line, UMR 106-01. The cells were stained by the avidin-biotin-complex technique for the presence of the enzyme. By this method, it was possible to identify cells producing collagenase. Synthesis, but not secretion, was found to be constitutive in these cells with the enzyme located intracellularly in cytoplasmic vesicles and the Golgi apparatus. The amount of collagenase contained within UMR cells and the number of cells synthesizing the enzyme were proportional to the concentration of fetal bovine serum in the incubating medium. When serum was withdrawn from the osteosarcoma cells, the content of collagenase decreased with time and the enzyme became undetectable by 48 h of serum depletion. The decrease in collagenase content could be completely reversed by resupplying serum to the cells. The collagenase promoting activity of serum could not be eliminated by adsorption on activated charcoal but was retained by a dialysis membrane with a 12,000 mol wt cutoff. A range of bone-seeking hormones or agents known to affect collagenase secretion was added to the medium in an attempt to mimic the effect of serum on collagenase accumulation. None of these agonists, including parathyroid hormone, could reproduce the effect of serum on these cells, although parathyroid hormone could act as a collagenase secretagogue in the presence or absence of serum. It is concluded that fetal bovine serum contains a yet unidentified factor or factors greater than 12,000 mol wt responsible for the continued synthesis of collagenase by UMR 106-01 cells.
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PMID:A serum factor promotes collagenase synthesis by an osteoblastic cell line. 164 67

The regulation of collagenase gene expression in the human osteosarcoma-derived osteoblastic cell lines MG-63, U2-OS and human fibroblast cell line IMR-90 was investigated by Northern blot analysis. Exposure of quiescent MG-63, U2-OS and IMR-90 cells to 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and 10% fetal calf serum (FCS) resulted in the induction of mRNA encoding collagenase. Epidermal growth factor (EGF) induced collagenase mRNA in the IMR-90 cell but not in the MG-63 and U2-OS cells. In the IMR-90 and MG-63 cells, EGF stimulated the transcription of the c-fos and c-jun genes encoding the transcriptional factors which interact directly with the promoter region of the human collagenase gene. Parathyroid hormone and 1,25-dihydroxy-vitamin D3 did not increase the collagenase mRNA level in both osteosarcoma cells. Recombinant interleukin-1 beta (rIL-1 beta) induced collagenase and c-jun but not c-fos mRNA in the MG-63 cell. The induction by rIL-1 beta was blocked by cycloheximide and dexamethasone. Transforming growth factor beta 1 blocked the FCS-induced collagenase gene expression but partially inhibited the rIL-1 beta-induced gene expression in the MG-63 cell. These results suggest that the collagenase activity is regulated not only by post-translational modification but also at the transcriptional level by the various factors in bone.
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PMID:[Regulation of collagenase gene expression in human osteosarcoma-derived osteoblastic cell lines]. 164 84

During continuous culture with serial passage, the human osteosarcoma cell line SaOS-2 showed a time-dependent decrease in skeletal alkaline phosphatase (ALP) activity. Because this was indicative of heterogeneity, subpopulations of SaOS-2 cells were isolated from replicate low-density cultures. The subpopulations were less heterogeneous and more stable (with respect to ALP) than the parent population. ALP specific activity in the subpopulations ranged from 0.05 to 2.3 U/mg protein, and cytochemical analyses indicated multiple steady-state levels of ALP activity per cell. The amount of ALP activity in SaOS-2 subpopulations was proportional to collagen production ([3H]proline incorporation into collagenase-digestible protein; r = .84, P less than .005), and to parathyroid hormone (PTH)-linked synthesis of cyclic adenosine monophosphate (cAMP) (r = .88, P less than .01). From these data, we inferred that ALP activity in SaOS-2 cells can provide a useful index of the osteoblastic phenotype, and that ALP activity, collagen production, and PTH-linked adenylate cyclase were coordinately regulated in these osteoblast-like osteosarcoma cells (ie, selection of subpopulations for ALP activity coselected for collagen synthesis and PTH-linked synthesis of cAMP). Further comparative studies showed that micromolar fluoride concentrations stimulated cell proliferation ([3H]thymidine incorporation into DNA) in low-ALP SaOS-2 subpopulations, but not in high-ALP cells (P less than .001), and that this differential sensitivity to fluoride was associated with an inverse correlation between fluoride-sensitive acid phosphatase and ALP activities (r = -.91, P less than .001).
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PMID:Skeletal alkaline phosphatase specific activity is an index of the osteoblastic phenotype in subpopulations of the human osteosarcoma cell line SaOS-2. 165 38

Peptides corresponding to selected sequences of the alpha 1 chain of the COOH propeptide of type I and type III human procollagen were synthesized and used as antigens to develop polyclonal and monoclonal antibodies. The antibodies were shown to be epitope specific using a peptide-based solid phase enzyme-linked immunoadsorbent assay. The antibodies were specific for the appropriate procollagens and the COOH propeptides isolated from serum-free culture supernatants of human skin fibroblasts. The rabbit antisera directed to the type I synthetic peptide bound the intact procollagen molecule and both the procollagen alpha 1(I) and alpha 2(I) chains after the reduction of the disulfide bonds. In addition, the antisera bound intact type I COOH propeptide, generated by bacterial collagenase treatment of procollagen, and the individual chains of the propeptide after reduction. In contrast, a monoclonal antibody to the type I peptide was able to bind only to the reduced form of the COOH propeptide. Both rabbit polyclonal and murine monoclonal antibodies directed to the type III synthetic peptide bound the intact and the individual chains of type III procollagen as well as the intact and reduced forms of the type III COOH propeptide. The antibodies have been used to detect procollagen synthesis in two human osteosarcoma cell lines and the differential expression of procollagen in the culture medium of rat lung fibroblasts grown in the presence or absence of glucocorticoids.
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PMID:Detection of procollagen biosynthesis using peptide-specific antibodies. 169 17

Proteolytic enzymes acting at physiologic pH (neutral proteases) are involved in both the formation and modeling of new bone and the remodeling of mature bone. In endochondral ossification systems such as growth-plate calcification, fracture healing, osteophyte formation, and demineralized bone matrix-induced osteogenesis, neutral proteases are predominantly involved in modifying proteins and proteoglycans in the extracellular matrix in preparation for calcification. These enzymes are of low molecular weight (below 30,000 Mr), are poorly charged, metal ion dependent, and appear to become active only after being released from chondrocytes. These neutral proteases may be distributed to the extracellular matrix in association with matrix vesicles that are derived from chondrocyte plasma membranes. A similar mechanism of calcification may also exist during malignant osteogenesis in an osteosarcoma; however, the cell producing the neutral protease in this lesion is the osteoblast and the matrix being synthesized is osteoid. In remodeling bone, osteoblasts secrete neutral collagenase (as an inactive enzyme) and produce not only additional proteases capable of activating the collagenase but also a collagenase inhibitor. Osteoblast collagenase or neutral protease may act to remove unmineralized osteoid from bone surfaces, thus facilitating its subsequent degradation by osteoclasts. The production of all these factors by osteoblasts appears to be regulated by calciotropic hormones (e.g., parathyroid hormone, 1,25-dihydroxyvitamin D, and calcitonin), possibly in a concerted fashion. Other possible functions of neutral proteases involve direct actions on cells or on specific molecules (growth factors) residing in the extracellular matrix.
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PMID:Neutral proteases in regenerating bone. 184 59

Previous studies demonstrated that tetracyclines (TCs) inhibited Type I (interstitial) and Type IV collagenases from different mammalian sources, but there are no studies of TCs effect on osteoblast collagenase (C'ase). The present study assessed the effect of TCs on C'ase activity from osteosarcoma cells. Semiconfluent UMR 106-01 cells were treated with minocycline or chemically modified tetracycline (CMT) at 10 micrograms/ml in the presence or absence of bovine parathyroid hormone, b-PTH-(1-34), at 10(-7)M for 24, 48, 72 and 96 hours. Media were collected at each time point and assayed following concentration, destruction of TIMP by reduction/alkylation, activation with p-aminophenylmercuric acetate (APMA), and incubation with 3H-methylated collagen substrate (approximately 100,000 dpm) at 27 degrees C for 18 hours. Collagenase activity from media was also analyzed by SDS-PAGE and fluorography. b-PTH appeared to stimulate C'ase 60-fold compared to controls; minocycline and CMT reduced PTH stimulation approximately 65% and 90%, respectively. Moreover, TCs incubated with partially purified osteoblastic collagenase directly, inhibited its activity in vitro as indicated by a lack of degradation to collagen alpha A chains. Therefore, TCs ability to inhibit bone resorption in organ culture, reported previously, may be due, in part, to reduced osteoblast collagenase activity.
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PMID:The effect of tetracyclines on collagenase activity in UMR 106-01 rat osteoblastic osteosarcoma cells. 196 17


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