Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The recent demonstration of estrogen receptors in bone derived cells has stimulated the study of direct effects of sex steroids on bone. We have shown direct stimulation of proliferation by 17 beta-estradiol (E2) of ROS 17/2.8 rat osteogenic osteosarcoma cells, and other bone-derived cells in culture, as well as sex-specific stimulation of diaphyseal bone in vivo by estrogen and testosterone, using [3H]thymidine incorporation into DNA and stimulation of the specific activity of creatine kinase as markers. ROS 17/2.8 cells were used as models of osteoblast-like cells to study the reciprocal modulation of stimulation of bone cell proliferation by sequential treatment by sex steroid and calciotrophic hormones. Pretreatment with 1,25(OH)2D3 and PTH augmented stimulation by E2, while pretreatment with PGE2 followed by E2 resulted in no additional stimulation. Reciprocally, pretreatment with E2 significantly reduced the response to PGE2 while showing an insignificant effect on the response to the other hormones. Gonadectomized Wistar-derived rats provided a useful model system for study of postmenopausal osteoporosis. In diaphyseal bone, [3H]thymidine incorporation and creatine kinase activity decreased 4 weeks after gonadectomy. At that time, a single i.p. injection of E2 in females, and testosterone in males, resulted in a highly significant increase in both these parameters within 24 h.
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PMID:Hormonal stimulation of bone cell proliferation. 225 46

PTH-related peptide (PTHrP) may be a major cause of the humoral hypercalcemia of malignancy. The circulating form of PTHrP is unknown, but mRNA analysis of tumor tissue suggests that multiple forms of PTHrP may exist. Therefore, we examined the ability of the full 141-amino acid protein as well as 2 amino-terminal fragments, PTHrP-(1-34) and PTHrP-(1-74), to increase cytosolic calcium ion concentrations ([Ca2+]i; assessed by aequorin luminescence) and stimulate cAMP accumulation in osteoblast-like rat osteosarcoma cells (ROS 17/2.8). PTH and all PTH-related peptides examined increased [Ca2+]i and cAMP in a concentration-dependent manner. The [Ca2+]i response to PTHrP-(1-34) closely resembled that to rat PTH-(1-34); both peptides produced biphasic responses. However, the responses to the longer PTHrP fragments generally were not biphasic. There were no significant differences among the three PTHrP forms in increasing [Ca2+]i or stimulating cAMP accumulation, although PTHrP-(1-74) was consistently weaker than the other two PTHrP peptides. PTHrP-(1-34) was more potent than rPTH-(1-34), which, in turn, was more potent than human PTH-(1-34) in increasing [Ca2+]i. However, PTHrP-(1-34) was not consistently more potent than either human PTH-(1-34) or rat PTH-(1-34) in stimulating cAMP accumulation. The inhibitory PTH analog bovine PTH-(3-34) attenuated both cAMP and [Ca2+]i responses to PTHrP-(1-34), but bovine PTH-(7-34) only reduced the [Ca2+]i response. Our data are generally consistent with PTHrP's acting through the PTH receptor, but differences in the effects of inhibitory PTH analogs on PTH and PTHrP action suggest as yet unexplained complexities, such as the existence of a PTH/PTHrP receptor family.
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PMID:Structure-function relationships for full-length recombinant parathyroid hormone-related peptide and its amino-terminal fragments: effects on cytosolic calcium ion mobilization and adenylate cyclase activation in rat osteoblast-like cells. 230 14

In the rat osteosarcoma cell line ROS 17/2.8, glucocorticoids increase the activity of the plasma membrane enzyme, alkaline phosphatase. To determine the mechanisms responsible for this effect, we have studied the actions of dexamethasone on alkaline phosphatase activity, immunoreactive protein, and steady-state mRNA levels. Dexamethasone treatment increased both specific activity of alkaline phosphatase and the cell surface expression of immunoreactive protein in a dose-dependent manner, with a half-maximal increase at 2 nM. Steady-state alkaline phosphatase mRNA levels were also increased in a dose-dependent manner. The time course of dexamethasone induction occurred relatively slowly, with a lag period of 12 h before any discernable effect on alkaline phosphatase mRNA levels. The rise in alkaline phosphatase mRNA levels was attributable entirely to changes in gene transcription, with no effect on message stability. Treatment of ROS 17/2.8 cells with actinomycin D completely abolished the dexamethasone-induced rise in alkaline phosphatase mRNA levels. Measurement of alkaline phosphatase mRNA degradation, by incubation of cells with the transcriptional inhibitor 5,6-dichloro-ribofuranosylbenzimidazole, indicated an apparent half-life of 24 h in both untreated and dexamethasone-stimulated cells. The protein synthesis inhibitors cycloheximide and puromycin blocked the dexamethasone induction of alkaline phosphatase mRNA. These data suggest that the dexamethasone-induced rise in alkaline phosphatase gene transcription requires the synthesis of an unknown mediator protein.
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PMID:Mechanism of glucocorticoid regulation of alkaline phosphatase gene expression in osteoblast-like cells. 231 98

The differential expression of mRNAs between the closely related rat osteosarcoma cell lines ROS 17/2.8 and ROS 25/1 was used to identify genes whose expression is associated with the osteoblast phenotype. Thymosin beta 4 cDNA was cloned from an ROS 17/2.8 complimentary DAN library on the basis of its differential hybridization with radiolabeled cDNA prepared from ROS 17/2.8 and ROS 25/1 cells. Northern blot analysis confirmed that thymosin beta 4, hitherto a putative immunodulatory hormone, was indeed differentially expressed. Steady state mRNA levels were severalfold higher in ROS 17/2.8 cells exhibiting an osteoblast-like phenotype, compared with the less osteoblast-like ROS 25/1. Thymosin beta 4 transcripts were also detected in rat UMR 106 osteosarcoma cells and in intact neonatal and fetal rat calvaria. Sequence analysis of the cDNA indicated that thymosin beta 4 transcripts may arise by processing at a more distal polyadenylation signal. Treatment of ROS 17/2.8 cells with dexamethasone increased, while addition of 1,25-dihydroxyvitamin D3 decreased thymosin beta 4 mRNA. The phenotype-dependent expression in the ROS cells and the response to steroid hormone suggest that thymosin beta 4 expression contributes to the osteoblast phenotype.
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PMID:Thymosin beta 4 is expressed in ROS 17/2.8 osteosarcoma cells in a regulated manner. 232 69

Low-level exposure to lead impairs longitudinal growth in children and in experimental animals. The proposed mechanisms include decreased osteocalcin secretion in response to 1 alpha,25-(OH)2 vitamin D3 and decreased response to insulin-like growth factor-I. The interaction of lead, 1 alpha,25-(OH)2 vitamin D3, and insulin-like growth factor-I was investigated in an osteoblast-like cell line from rat osteosarcoma, ROS 17/2.8. Cells were cultured 24 hr in a serum-free medium with lead, 1 alpha,25-(OH)2 vitamin D3, and insulin-like growth factor-I. 1 alpha,25-(OH)2 vitamin D3 (10 nM) evoked a 4-5 X increase in osteocalcin secretion and a 100% increase in cellular alkaline phosphatase activity but no increase in DNA/cell layer. Insulin-like growth factor-I (92.5 ng/ml) evoked a 100% increase of osteocalcin secretion and a 20% increase in cellular DNA contents but no change in cellular alkaline phosphatase activity. Basal and stimulated cellular osteocalcin secretion, cellular alkaline phosphatase activity, and DNA contents were significantly inhibited by addition of 1-10 microM lead. The data are consistent with a toxic effect of lead on osteoblastic function and the cellular responses to 1 alpha,25-(OH)2 vitamin D3 and insulin-like growth factor-I. This interaction may be relevant to impaired childhood growth at low levels of lead exposure.
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PMID:Lead inhibits the basal and stimulated responses of a rat osteoblast-like cell line ROS 17/2.8 to 1 alpha,25-dihydroxyvitamin D3 and IGF-I. 233 May 89

Using microelectrode techniques, we have observed that the application of serum or alpha 2-macroglobulin (alpha 2M) induces transient hyperpolarizations in the membrane potential of a rat osteosarcoma clone (ROS 17/2). Hyperpolarizations arose from activation of Ca2+-dependent K+ channels by transient increases in the concentration of intracellular free Ca2+. Hyperpolarizing spikes were observed for several h following the addition of fetal bovine serum (FBS) to cell cultures. Application of small volumes of FBS or alpha 2M rapidly induced synchronized bursts of hyperpolarizing spikes. No response was elicited by serum-free medium, latex beads, or bovine serum albumin (BSA). Immunofluorescence labeling patterns were consistent with the receptor-mediated endocytosis of alpha 2M but not BSA. The ligand specificity and kinetics of these hyperpolarizations suggest that they are associated with a receptor-mediated event, possibly an early stage of receptor-mediated endocytosis.
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PMID:Serum and alpha 2-macroglobulin induce transient hyperpolarizations in the membrane potential of an osteoblastlike clone. 244 77

We have reported previously that serum and alpha 2-macroglobulin (alpha 2M) induce Ca2+-activated hyperpolarizations in the membrane potential of a clonal rat osteosarcoma cell line (ROS 17/2) (Dixon and Aubin, J. Cell, Physiol., 132:215-225, 1987). In this report, we describe morphological changes that accompany these hyperpolarizations. Both cell surface blebbing (zeiosis) and transient hyperpolarizations were induced by application of 10% fetal bovine serum (FBS) or alpha 2M; neither was induced by serum-free medium, a suspension of latex beads, or purified bovine serum albumin. Following a brief application of FBS or alpha 2M at time 0, electrical activity typically occurred between 7-40 s and was always followed by blebbing activity that began at 30 s and persisted for 3-5 min. In contrast, continuous exposure to FBS resulted in the persistence of both blebbing activity and transient hyperpolarizations for periods of at least several hours. Scanning electron microscopy (SEM) revealed that the blebs appeared concomitantly with the disappearance of microvilli and the appearance of surface pits that measured 100-300 nm in diameter. Coated pits and vesicles, similar in size to the pits observed by SEM, were observed using transmission electron microscopy (TEM). By TEM, blebs were found to contain few organelles other than centrally located free ribosomes. Fluorescence microscopy of nitrobenzooxadizole-phallacidin-labeled cells indicated that blebs contained filamentous actin and that microfilament bundles remained primarily on the substratum side of blebbed cells. We propose that blebbing results from a dynamic local reorganization of microfilaments initiated by ligand-induced transient increases in intracellular Ca2+.
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PMID:Membrane blebbing is associated with Ca2+-activated hyperpolarizations induced by serum and alpha 2-macroglobulin. 244 13

Rat osteogenic sarcoma cells have been used widely as a model system to study actions of 1,25(OH)2D3 and other hormones in osteoblastlike cells. However, some of the pleiotypic manifestations of hormones in these cells vary greatly dependent upon the cell population density and other conditions of culture. Therefore, we have studied the effect of cell density on the relationship between 1,25(OH)2D3 and the initial 45Ca accumulation in ROS 17/2 cells in order to establish conditions suitable for studying the effect of 1,25(OH)2D3 on calcium fluxes in these cells. Cells were grown in the presence and absence of 1,25(OH)2D3 for 48 hours and then incubated for 4 min in the culture medium containing 0.5 microCi/ml of 45CaCl2. In high population density cultures, 0.25-1.0 pg/ml of 1,25(OH)2D3 stimulated the intracellular accumulation of 45Ca (cpm/mg protein), whereas 80 pg/ml or higher concentrations inhibited accumulation of 45Ca. In low density cultures, concentrations less than 80 pg/ml had no effect, 80-120 pg/ml increased the intracellular accumulation, and as much as 200 pg/ml failed to show the inhibitory effect. These results indicate that the ROS 17/2 cell responses to 1,25(OH)2D3 are biphasic--low concentrations stimulating and high concentrations inhibiting 45Ca accumulation. The sensitivity of the cells to 1,25(OH)2D3 increases as the cell population density increases. These observations suggest that the culture density and dose-response relationship must be carefully defined in in vitro studies utilizing osteogenic cell culture systems.
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PMID:Cell density-dependent vitamin D effects on calcium accumulation in rat osteogenic sarcoma cells (ROS 17/2). 244 55

This study compares the metabolism of [14C]-arachidonic acid between PGE2 synthesizing (ROS 17/2.8) and nonsynthesizing (ROS 25/1) osteosarcoma cell lines. In both cell lines: (a) 90% of [14C]-arachidonic acid was taken up at 24 h. (b) More than 90% of the label was associated with phospholipids. (c) [14C]-arachidonic acid was rapidly taken up by phosphatidylcholine which reached the highest specific activity around 5 h while the labeling of other phospholipids was still increasing at 24 h. (d) Twenty-four hours after addition of [14C]-arachidonic acid only 4% of the label was associated with triacylglycerols in ROS 25/1 and 0.3% in ROS 17/2.8 cells. The calcium ionophore A23187 enhanced the release of [14C]-arachidonic acid from phospholipids in the PGE synthesizing osteoblastic cells (ROS 17/2.8 and 2/3) but had no effect in nonosteoblastic cells (ROS 24/1 and 25/1). ROS 17/2.8 and 2/3 cells converted the released arachidonic acid as well as exogeneously added arachidonic acid into PGE2. PGE2 synthesis depended on arachidonic acid concentration. Among bone resorbing agents, parathyroid hormone and 1,25(OH)2D3 had no effect on PGE synthesis, whereas thrombin and rabbit serum stimulated PGE2 production. The effect of rabbit serum was abolished by heat inactivation. The findings of this study indicate that the difference in PGE production between the osteoblastic and nonosteoblastic osteosarcoma cells are due mainly to differences in arachidonic acid conversion to PGE2.
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PMID:Clonal differences in prostaglandin synthesis among osteosarcoma cell lines. 245 9

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] regulates the synthesis of bone gamma-carboxyglutamic acid (Gla) protein (BGP) by osteoblastic cells. In this study we examined the effect of cAMP, alone and in combination with 1,25-(OH)2D3, on the regulation of BGP mRNA levels in ROS 17/2 rat osteosarcoma cells. Elevation of intracellular cAMP levels by cAMP analogs or by isobutylmethylxanthine (IBMX), forskolin, or PTH, resulted in increased BGP mRNA levels and BGP secretion after 1 day of treatment. The effects of these agents were additive with 1,25-(OH)2D3 in stimulating BGP gene expression. After 4 days of treatment, pertussis toxin (PT) and 1,25-(OH)2D3 were synergistic in stimulating BGP mRNA, and the effect of PT could be mimicked by (Bu)2cAMP, IBMX, forskolin, cholera toxin, and to a lesser extent by PTH. The effect of 1-day treatment with cAMP alone and the synergistic effect with 1,25-(OH)2D3 on the stimulation of BGP mRNA were dependent on cell density, while basal and 1,25-(OH)2D3-stimulated synthesis were not. Cyclic AMP inhibited ROS 17/2 cell growth after 1 day of treatment, an effect that was also dependent on initial cell density. After 4 days of treatment, 1,25-(OH)2D3, cAMP, and PT all demonstrated inhibition of cell growth. When cells were treated with actinomycin D, both 1,25-(OH)2D3 and cAMP stimulation of BGP mRNA were blocked. In addition, neither agent was effective in enhancing BGP mRNA stability when prestimulated cells were exposed to actinomycin D.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bone Gla protein messenger ribonucleic acid is regulated by both 1,25-dihydroxyvitamin D3 and 3',5'-cyclic adenosine monophosphate in rat osteosarcoma cells. 246 56


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