UMLS:C0029463 - FACTA Search

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

Interleukin 1 (IL-1) is a proinflammatory cytokine which can elicit proliferative, differentiative, or metabolic responses. The molecular mechanisms by which IL-1 signals are transduced from the plasma membrane to the nucleus, although extensively studied, have not been completely elucidated. We previously demonstrated that human osteosarcoma Saos-2 cells incubated with IL-1 presented a rapid and transient increase of phospholipase C activity exclusively at the nuclear level. Moreover, we presented evidence that not only the canonical inositol lipid signalling pathway was involved, but also the D3-phosphorylated lipids generated by phosphatidylinositol 3-kinase (PI 3-kinase) were affected. The results of this study indicate that in Saos-2 cells PI 3-kinase is recruited and activated by IL-1 receptor I (IL-1RI) through binding of the SH2 domains to the consensus sequence on the C-terminal tail of the receptor, and that Tyr-479 is essential for PI 3-kinase activation. Moreover, IL-1 treatment triggers PI 3-kinase translocation to the nucleus; this event is rapid and transient in cells expressing high levels of IL-1RI (Saos-2/IL-1R) as well as in untransfected cells, although to a lesser extent. The data, based on immunochemical and immunocytochemical quantitative methods, indicate that PI 3-kinase translocation to the nucleus depends on PI 3-kinase activation. In fact, inactivation by two independent mechanisms, addition of specific PI 3-kinase inhibitors, or overexpression of a mutant form of IL-1RI, resulted in a substantial inhibition of PI 3-kinase translocation to the nucleus. These data suggest that PI 3-kinase recruitment by the activated receptor is a limiting step in PI 3-kinase activation and nuclear translocation. This early event in the IL-1 signalling mechanisms confirms that D3 inositides, as well as canonical inositides produced by nuclear phospholipase C isoforms, are involved in this pathway of activation of transcription factors.
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PMID:Phosphatidylinositol 3-kinase translocation to the nucleus is an early event in the interleukin-1 signalling mechanism in human osteosarcoma Saos-2 cells. 1047 Mar 65

Osteocalcin (OC) is an abundant noncollagenous bone matrix protein, yet its function is largely unknown. However, targeted ablation of two OC genes in mice lead to increased bone formation (Ducy et al. Nature 382:448-452; 1996). This implied that OC inhibits osteoblast activity, and that these cells express an OC receptor. In order to characterize the putative OC receptor, we used the Cytosensor microphysiometer to measure responses of a proliferative-stage, conditionally immortalized human osteoblast cell line (HOB-03-C5) to purified bovine OC (bOC). The Cytosensor measures a change in the extracellular acidification rate, which is primarily a measurement of metabolic activity. Treatment of the HOB cells for 5-60 sec with 0.17 micromol/L bOC generated a time-dependent, transient increase in the acidification rate that became optimal after 25 sec. Likewise, treatment of the cells for 25 sec with 0.021 to 1.9 micromol/L bOC caused a dose-dependent 70% increase in the acidification rate. Pre-treatment of the cells for 2 h with inhibitors of adenylyl cyclase, phospholipase C, and intracellular calcium release inhibited the response of the cells to bOC by 50%-100%, which suggested that the putative OC receptor was coupled to a G-protein. These observations from the Cytosensor were confirmed by measuring intracellular cyclic-adenosine monophosphate (cAMP) concentrations in response to bOC. Treatment of the cells for 10 min with bOC decreased basal cAMP levels by 65% in a dose-dependent manner with an IC50 of 0.22 microM. However, cotreatment of the cells with forskolin, which activates adenylyl cyclase, blunted this suppression. Moreover, pretreatment of the cells with pertussis toxin for 48 h, which inhibits G(alpha)i proteins, reversed the suppressive effects of bOC on cAMP production. Treatment of the HOB cells for 48 h with 0.19 to 1.5 micromol/L bOC caused a dose-dependent 40% decrease in alkaline phosphatase activity with an IC50 of 0.21 micromol/L, which suggested that OC may inhibit HOB activity. Finally, although the maturation stage, conditionally immortalized HOB-02-C1 cells also responded to bOC as measured by the Cytosensor, two osteosarcoma cell lines, SaOS-2 and ROS 17/2.8, exhibited a 5- to 10-fold lower response to the bone matrix protein, suggesting that the putative OC receptor was downregulated in these cells. However, all of these bone cell lines responded to parathyroid hormone treatment. In conclusion, these results provide evidence that the HOB cells express an OC receptor, and that this receptor appears to be coupled to a G(alpha)-protein.
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PMID:Evidence that conditionally immortalized human osteoblasts express an osteocalcin receptor. 1057 73

The effect of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7), a widely used calmodulin inhibitor, on intracellular free Ca(2+)levels ([Ca(2+)](i)) in MG63 human osteosarcoma cells was explored using fura-2 as a Ca(2+)probe. W-7 (20-1000 micro m) induced an increase in [Ca(2+)](i)in a dose-dependent manner, with an EC(50)of 100 microm. The [Ca(2+)](i)signal comprised an initial rise and a sustained plateau without significant decay within 5 min. External Ca(2+)removal decreased the Ca(2+)signals by reducing the peak and sustained phase, indicating W-7-activated intracellular Ca(2+)release and extracellular Ca(2+)influx. W-7 (500 microm) failed to induce a [Ca(2+)](i)increase in a Ca(2+)-free medium after pre-treatment with thapsigargin (1 microm), an endoplasmic reticulum Ca(2+)pump inhibitor. Conversely, W-7 pre-treatment abolished the Ca(2+)release induced by thapsigargin. This suggests that W-7 (500 microm ) released internal Ca(2+)mainly from the endoplasmic reticulum. The addition of 3 mm Ca(2+)increased [Ca(2+)](i)dose-dependently after preincubation with 20-1000 microm W-7 in a Ca(2+)-free medium, implying that W-7 induced capacitative Ca(2+)entry. W-7-induced Ca(2+)release was not altered by inhibiting phospholipase C with 2 microm 1-(6-((17 beta - 3-methoxyestra-1,3, 5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione) (U73122). Tryphan blue assay demonstrated that W-7 (200 microm) caused gradual cell death within 30 min of the initial drug exposure. Together, it was found that W-7 induced [Ca(2+)](i)increases in human osteosarcoma cells by releasing internal Ca(2+)from the endoplasmic reticulum, and also by triggering Ca(2+)influx. W-7 may be cytotoxic to osteosarcoma cells.
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PMID:Ca(2+) mobilization induced by W-7 in MG63 human osteosarcoma cells. 1098 91

The effect of the estrogen diethylstilbestrol (DES) on intracellular Ca(2+) concentrations ([Ca(2+)](i)) in Madin Darby canine kidney (MDCK) cells was investigated, using the fluorescent dye fura-2 as a Ca(2+) indicator. DES (10-50 microM) evoked [Ca(2+)](i) increases in a concentration-dependent manner. Extracellular Ca(2+) removal inhibited 45 +/- 5% of the Ca(2+) response. In Ca(2+)-free medium, pretreatment with 50 microM DES abolished the [Ca(2+)](i) increases induced by 2 microM carbonylcyanide m-chlorophenylhydrazone (CCCP; a mitochondrial uncoupler) and 1 microM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor); and pretreatment with CCCP and thapsigargin partly inhibited DES-induced [Ca(2+)](i) signals. Adding 3 mM Ca(2+) increased [Ca(2+)](i) in cells pretreated with 50 microM DES in Ca(2+)-free medium, suggesting that DES may induce capacitative Ca(2+) entry. 17beta-Estradiol (2-20 microM) increased [Ca(2+)](i), but 100 microM diethylstilbestrol dipropionate had no effect. Pretreatment with the phospholipase C inhibitor U73122 (1 microM) to abolish inositol 1,4,5-trisphosphate formation inhibited 30% of DES-induced Ca(2+) release. DES (20 microM) also increased [Ca(2+)](i) in human normal hepatocytes and osteosarcoma cells. Cumulatively, this study shows that DES induced rapid and sustained [Ca(2+)](i) increases by releasing intracellular Ca(2+) and triggering extracellular Ca(2+) entry in renal tubular cells.
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PMID:Effect of diethylstilbestrol (DES) on intracellular Ca(2+) levels in renal tubular cells. 1118 39

The effect of fendiline, an anti-anginal drug, on cytosolic free Ca(2+) levels ([Ca(2+)](i)) in MG63 human osteosarcoma cells was explored by using fura-2 as a Ca(2+) indicator. Fendiline at concentrations between 1 and 200 microM increased [Ca(2+)](i) in a concentration-dependent manner and the signal saturated at 100 microM. The Ca(2+) signal was inhibited by 65+/-5% by Ca(2+) removal and by 38+/-5% by 10 microM nifedipine, but was unchanged by 10 microM La(3+) or verapamil. In Ca(2+)-free medium, pre-treatment with 1 microM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor) to deplete the endoplasmic reticulum Ca(2+) store inhibited fendiline-induced intracellular Ca(2+) release. The Ca(2+) release induced by 50 microM fendiline appeared to be independent of IP(3) because the [Ca(2+)](i) increase was unaltered by inhibiting phospholipase C with 2 microM U73122. Collectively, the results suggest that in MG63 cells fendiline caused an increase in [Ca(2+)](i) by inducing Ca(2+) influx and Ca(2+) release in an IP(3)-independent manner.
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PMID:The anti-anginal drug fendiline increases intracellular Ca(2+) levels in MG63 human osteosarcoma cells. 1124 76

When osteoblasts are cultured on surfaces of increasing microroughness, they exhibit decreases in proliferation, increases in differentiation and local factor production, and enhanced response to 1alpha,25(OH)(2)D(3). The cells interact with surfaces through integrins, which signal by the same pathways used by 1alpha,25(OH)(2)D(3), including protein kinase C via phospholipase C and protein kinase A via phospholipase A(2). This provides opportunities for crosstalk that may contribute to the synergistic effects of surface roughness and the vitamin D metabolite. Because these pathways converge at mitogen-activated protein kinase (MAPK), we tested the hypothesis that the extracellular signal-regulated kinase (ERK1/2) subclass of MAPKs mediates the effects of surface roughness and 1alpha,25(OH)(2)D(3). MG63 osteoblast-like osteosarcoma cells were cultured on commercially pure Ti disks with various surface roughnesses: pretreatment (PT; 0.6 microm average roughness [Ra]), coarse grit-blasted and acid-etched (SLA; 4 microm RA), and titanium plasma-sprayed (TPS; 5.2-microm R(a)). At confluence, cells were treated for 24 h with control media or media containing 10(-7) M 1alpha,25(OH)(2)D(3). One-half of the cultures received 1 microm or 10 microm PD98059, a specific inhibitor of the ERK family of MAPKs. PD98059 alone did not affect proliferation, osteocalcin production, or production of transforming growth factor-beta1 or nitric oxide, regardless of the surface roughness. Alkaline phosphatase was reduced by the inhibition of the ERK family kinases on all surfaces to a comparable extent. However, when PD98059 was added to the cultures with 1alpha,25(OH)(2)D(3), the effects of the seco-steroid were blocked, including the synergistic increases seen in MG63 cells cultured on SLA or TPS. These results indicate that ERK1/2 MAPK is required for the maintenance of alkaline phosphatase at control levels and that the effects of 1alpha,25(OH)(2)D(3) are mediated by ERK1/2. However, the effects of surface roughness are not due to the ERK family of MAPKs. This suggests that alternative pathways may be used, including those mediated by other MAPK subclasses.
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PMID:Osteoblast response to titanium surface roughness and 1alpha,25-(OH)(2)D(3) is mediated through the mitogen-activated protein kinase (MAPK) pathway. 1137 60

The effect of histamine on intracellular free Ca2+ levels ([Ca2+](i)) in MG63 human osteosarcoma cells was explored using fura-2 as a Ca2+ dye. Histamine increased ([Ca2+](i)) in a concentration-dependent fashion with an EC(50) value of 0.5 microM. Extracellular Ca2+ removal inhibited the ([Ca2+](i)) signals. Histamine failed to increase ([Ca2+](i)) in Ca2+-free medium after cells were pretreated with thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor). Addition of Ca2+ induced concentration-dependent ([Ca2+](i)) increases after preincubation with histamine in Ca2+-free medium. Histamine-induced intracellular Ca2+ release was abolished by inhibiting phospholipase C with 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122). The ([Ca2+](i)) increase induced by histamine in Ca2+ medium was abolished by cimetidine, but was not altered by pyrilamine, nifedipine, verapamil, and La(3+). Together, this study shows that histamine increased in ([Ca2+](i)) in osteosarcoma cells by stimulating H2 histamine receptors. The Ca2+ signal was caused by Ca2+ release from the endoplasmic reticulum in a phospholipase C-dependent manner. The Ca2+ release was accompanied by Ca(2+) influx.
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PMID:Mechanisms of histamine-induced intracellular Ca2+ release and extracellular Ca2+ entry in MG63 human osteosarcoma cells. 1137 83

The effect of clomiphene, an ovulation-inducing agent, on cytosolic free Ca2+ levels ([Ca2+]i) in MG63 human osteosarcoma cells was explored by using fura-2 as a Ca2+ indicator. Clomiphene at concentrations between 5-75 microM increased [Ca2+]i in a concentration-dependent manner with an EC50 of 50 microM. The [Ca2+]i signal consisted of an initial rise and a sustained phase. Ca2+ removal reduced the Ca2+ signal by 40+/-10%. The [Ca2+]i increase induced by 50 microM clomiphene was inhibited by 80+/-5% by 10 microM nifedipine, but was insensitive to 50 microM La3+ or 10 microM verapamil. In Ca2+-free medium, pretreatment with 50 microM brefeldin A (to disrupt the Golgi complex Ca2+ store), 1 microM thapsigargin (to inhibit the endoplasmic reticulum Ca2+ pump), and carbonylcyanide m-chlorophenylhydrazone (CCCP; to uncouple mitochondria) inhibited 51+/-3% of 50 microM clomiphene-induced Ca2+ release; conversely, pretreatment with 50 microM clomiphene abolished the [Ca2+]i increase induced by thapsigargin, CCCP, and brefeldin A. The Ca2+ release-induced by 50 pM clomiphene was unchanged by inhibition of phospholipase C with 2 microM 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122). Collectively, the results suggest that clomiphene increased [Ca2+]i, in osteoblast-like cells, by releasing intracellular Ca2+ in a phospholipase C-independent manner and by causing nifedipine-sensitive Ca2+ influx.
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PMID:Clomiphene, an ovulation-inducing agent, causes [Ca2+]i increases in human osteoblast-like cells. 1153 Sep 46

We have previously demonstrated that glucocorticoids increased G(q/11)alpha protein expression and phospholipase C activity in the rat osteosarcoma cell line UMR 106-01. In this study, we demonstrated that G(11)alpha is the primary G(q)-subtype family member expressed in UMR cells. Dexamethasone treatment increased the expression of G(11)alpha protein in both a time- and a dose-dependent manner. Glucocorticoid treatment significantly increased the half-life of G(11)alpha protein from 20.3 to 63 h. Steady-state G(11)alpha mRNA level was also increased by glucocorticoid treatment by approximately 70%. This change was not the result of changes in RNA stability but rather the result of increased transcription, because the glucocorticoid-mediated upregulation of G(11)alpha mRNA was blocked by the transcription inhibitor actinomycin D. The dexamethasone induction of G(11)alpha mRNA occurred after a time lag of 12-24 h and was blocked by the protein synthesis inhibitor cycloheximide. These results suggest that the dexamethasone-induced rise in G(11)alpha protein results primarily from changes in the degradation rate of the protein, whereas changes in G(11)alpha mRNA play a smaller role and require de novo synthesis of regulatory protein(s).
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PMID:Mechanisms of regulation of G(11)alpha protein by dexamethasone in osteoblastic UMR 106-01 cells. 1173 79

Leukotactin-1 (Lkn-1)/CCL15 is a recently cloned CC-chemokine that binds to the CCR1 and CCR3. Although Lkn-1 has been known to function as a chemoattractant for neutrophils, monocytes and lymphocytes, its cellular mechanism remains unclear. To understand the mechanism of Lkn-1-induced chemotaxis signaling, we examined the chemotactic activities of human osteogenic sarcoma cells expressing CCR1 in response to Lkn-1 using inhibitors of signaling molecules. Inhibitors of G(i)/G(o) protein, phospholipase C (PLC) and protein kinase Cdelta (PKCdelta) inhibited the chemotactic activity of Lkn-1 indicating that Lkn-1-induced chemotaxis signal is transduced through G(i)/G(o) protein, PLC and PKCdelta. The activities of PLC and PKCdelta were also enhanced by Lkn-1 stimulation. Chemotactic activity of Lkn-1 was inhibited by the treatment of cycloheximide and actinomycin D suggesting that newly synthesized proteins are needed for chemotaxis. Nuclear factor-kappaB (NF-kappaB) inhibitor reduced chemotactic activity of Lkn-1. DNA binding activity of NF-kappaB was also enhanced by Lkn-1 stimulation. These results suggest that Lkn-1 transduces the signal through G(i)/G(o) protein, PLC, PKCdelta, NF-kappaB and newly synthesized proteins for chemotaxis.
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PMID:Leukotactin-1/CCL15-induced chemotaxis signaling through CCR1 in HOS cells. 1194 14

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