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 rat osteosarcoma cell line UMR-106 has an osteoblast-like phenotype and possesses parathyroid hormone (PTH)-responsive dual signal transduction systems [adenosine 3',5'-cyclic monophosphate-dependent protein kinase (PKA) and calcium-protein kinase C (Ca-PKC)]. These cells transport inorganic phosphate (Pi) by a Na(+)-dependent carrier under stimulation by PTH. The present study aimed to clarify PTH-responsive signal transduction mechanisms in the regulation of Na(+)-dependent Pi transport by PTH in UMR-106 cells. Exposure of these cells to 10(-7) mol/l PTH induced a significant increase in Pi uptake within 30 min of incubation and it became maximal after 2 h. Parathyroid hormone (10(-9)-10(-7) mol/l) stimulated Pi uptake dose dependently. Activation of PKC by 12-O-tetradecanoyl phorbol-13-acetate (TPA) also increased Pi uptake in time- and dose-dependent manners similar to PTH. In contrast, neither PKA activation by 10(-4) mol/l forskolin or by 10(-4) mol/l dibutyryladenosine 3',5'-cyclic monophosphate nor calcium ionophore treatment with 10(-7) mol/l A23187 or with 10(-7) mol/l ionomycin during 3-h incubations affect Pi uptake, except its increase by 10(-4) mol/l forskolin at a 3-h incubation. These agents had no influence on Pi uptake even in combined treatments with TPA. The PTH-induced increase in Pi uptake was abolished almost completely by pretreating cells with PKC inhibitors, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride (H-7) (50 mumol/l) or staurosporin (10 and 50 nmol/l), and by down-regulating PKC with a prolonged TPA treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Involvement of protein kinase C in the stimulation of sodium-dependent phosphate transport by parathyroid hormone in osteoblast-like cells. 780 49

Endothelins (ETs) (ET-1, ET-2, and ET-3), a family of 21-amino acid peptides, mediate a host of biological responses by binding to specific cell surface receptors termed ETA and ETB. Because a role for ET in bone remodeling has been suggested, the present study was undertaken (a) to characterize ET receptors and their responses in the rat osteosarcoma cell line ROS 17/2.8 and (b) to study their regulation by 1,25-dihydroxy-vitamin D3. Binding studies using 125I-ET-1 (a nonselective agonist) and 125I-IRL-1620 (an ETB receptor-selective agonist) indicated that these cells display high affinity ETA and ETB receptors in the ratio of 3:1. Addition of ET-1 or sarafotoxin 6c to myo-[3H]inositol-labeled cells resulted in an increase in inositol phosphate accumulation as well as in intracellular Ca2+ release, suggesting that these receptors are coupled to phospholipase C. In addition, ET-1 but not sarafotoxin 6c induced a modest increase in the expression of osteocalcin protein that was completely blocked by BQ123 (an ETA receptor-selective antagonist), indicating that activation of ETA receptors plays a role in the induction of osteocalcin. Treatment of ROS osteoblasts with 10 nM 1,25-dihydroxy-vitamin D3 for 14 hr resulted in a significant (> 50%) decrease in 125I-ET-1 and 125I-IRL-1620 binding. This decrease in binding was shown to be due to a decrease in the number of ET receptors, with no change in affinity. Although both ETA and ETB receptors were down-regulated in response to 1,25-dihydroxy-vitamin D3, only ETA receptor mRNA levels were significantly decreased, with very little change in ETB mRNA levels. These data indicate that ROS osteoblasts display both ETA and ETB receptors that are functional. Induction of osteocalcin was primarily mediated by ETA receptors, and these receptors were also down-regulated at the mRNA level by 1,25-dihydroxy-vitamin D3.
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PMID:Identification and characterization of endothelin receptors on rat osteoblastic osteosarcoma cells: down-regulation by 1,25-dihydroxy-vitamin D3. 787 34

We assessed the significance of Ca and phosphate (P(i)) as determinants of (1) the amount of skeletal alkaline phosphatase (ALP) activity in SaOS-2 (human osteosarcoma) cells and normal human bone cells, and (2) the release of ALP activity from the cells into the culture medium. After 24 h in serum-free BGJb medium containing 0.25-2 mM P(i), the specific activity of ALP in SaOS-2 cells was proportional to P(i) concentration (r = 0.99, p < 0.001). The P(i)-dependent increase in ALP activity was time dependent (evident within 6 h) and could not be attributed to decreased ALP release, since P(i) also increased the amount of ALP activity released (r = 0.99, p < 0.001). Parallel studies with Ca (0.25-2.0 mM) showed that the amount of ALP activity released from SaOS-2 cells was inversely proportional to the concentration of Ca (r = -0.85, p < 0.01). This effect was rapid (i.e., observed within 1 h) and could not be attributed to a decrease in the amount of ALP activity in the cells. Phase distribution studies showed that the effect of low Ca to increase ALP release reflected increases in the release of both hydrophilic ALP (i.e., anchorless ALP, released by phosphatidylinositol-glycanase activity) and hydrophobic ALP (i.e., phosphatidylinositol-glycan-anchored ALP, released by membrane vesicle formation). The range of Ca-dependent changes in ALP-specific activity was much smaller than the range of P(i)-dependent changes. The observed correlation between skeletal ALP-specific activity and P(i) was not unique to osteosarcoma cells or to P(i). Similar effects were seen in normal human bone cells in response to P(i) (r = 0.99, p < 0.001) and in SaOS-2 cells in response to a variety of P(i) esters and analogs (e.g., beta-glycero-P(i) and molybdate). Further studies indicated that the effects of phosphoryl compounds on ALP-specific activity could not be correlated with effects on ALP reaction kinetics, cell proliferation, or acid phosphatase activity and that the beta-glycero-P(i)-dependent increase in ALP activity was blocked by cycloheximide but not actinomycin D. Together these data suggest that the function of skeletal ALP may be regulated by P(i) and that Ca may be involved in ALP release.
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PMID:Specific activity of skeletal alkaline phosphatase in human osteoblast-line cells regulated by phosphate, phosphate esters, and phosphate analogs and release of alkaline phosphatase activity inversely regulated by calcium. 803 Apr 37

Previous studies have demonstrated that parathyroid hormone (PTH) and human alpha-thrombin mobilize intracellular calcium from distinct pools in UMR 106-H5 rat osteosarcoma cells. The present studies were designed to explore the molecular basis of this differential signaling. Maximally effective concentrations of both PTH (240 nM) and thrombin (10 U/ml) produced a rapid intracellular free calcium (Cai++) transient (a 2- to 3-fold increase) that was inhibited by pretreatment with the phospholipase C inhibitor 1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]- 1H-pyrrole-2,5-dione (U73,122) in a dose-dependent manner (IC50 = 3 microM). Inhibition by U73,122 was not associated with a change in PTH-stimulated adenylate cyclase activity, whereas inositol phosphate accumulation, detected only in response to thrombin, was inhibited 23 to 45%. Prior exposure of cells for 5 min with the protein kinase C activators phorbol 12-myristate 13-acetate (8-80 nM) and phorbol 12,13-dibutyrate (80 nM) weakly inhibited (< or = 30%) the peak Cai++ increase in response to thrombin but completely blocked the Cai++ response to PTH. In contrast, 12-myristate 13-acetate produced a 1.55-fold increase in the maximal stimulatory effect of PTH on adenylate cyclase activity. These data suggest that activation of phospholipase C is a prerequisite for both PTH- and thrombin-stimulated increases in Cai++ and that protein kinase C differentially regulates the ability of these agents to raise Cai++. Collectively the results support the notion that the IP3/calcium mobilizing pathways utilized by PTH and thrombin are compartmentalized.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A novel phospholipase C inhibitor and phorbol esters reveal selective regulation of thrombin- and parathyroid hormone-stimulated signaling pathways in rat osteosarcoma cells. 816 21

Previous in vitro studies have shown that the effect of fluoride to increase avian osteoblast-like cell proliferation was dependent on the phosphate concentration. In vitro studies have further revealed that fluoride could also have direct effects on osteoblast-like cells to increase phosphate uptake and transiently increase cytosolic calcium. The current studies were intended to determine whether fluoride could increase net 45Ca uptake by human osteosarcoma (SaOS-2) cells and, if so, whether those effects would also be phosphate dependent. The results of these studies indicate that fluoride increased net 45Ca uptake by SaOS-2 cells, with biphasic dose and time dependencies. After 30 minutes of exposure, net 45Ca uptake was increased to a greater extent by 50 microM fluoride (217 +/- 16% of control, P < 0.001) than by 200 microM fluoride; and the stimulatory effect of 100 microM fluoride on net 45Ca uptake was greater after 20 minutes (187 +/- 22% of control, P < 0.001) than after 60 minutes (122 +/- 7% of control, P < 0.05). These effects of fluoride to increase net 45Ca uptake were dependent on the phosphate concentration in the medium. Fluoride had no effect on net 45Ca uptake in medium containing 0.4 mM phosphate, but increased net 45Ca uptake in medium containing 1.2 or 2.0 mM phosphate (P < 0.005). As the phosphate concentration was increased, the biphasic fluoride dose-response curve was shifted to a lower range of fluoride concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fluoride increases net 45Ca uptake by SaOS-2 cells: The effect is phosphate dependent. 824 71

The rat osteosarcoma cell line UMR-106-01 has an osteoblast-like phenotype. When grown in monolayer culture these cells transport inorganic phosphate and L-alanine via Na(+)-dependent transport systems. Exposure of these cells to a low phosphate medium for 4 h produced a 60-70 per cent increase in Na(+)-dependent phosphate uptake compared to control cells maintained in medium with a normal phosphate concentration. In contrast, Na(+)-dependent alanine uptake and Na(+)-independent phosphate uptake were not changed during phosphate deprivation. The increased phosphate uptake was due, in part, to an increased Vmax and was blocked completely by pretreatment with cycloheximide (70 microM). In these cells recovery of intracellular pH after acidification with NH4Cl is due primarily to the Na+/H+ exchange system. The rate of this recovery process, monitored with a pH sensitive indicator (BCECF), was decreased by more than 50 per cent in phosphate-deprived cells compared to controls indicating that Na+/H+ exchange was inhibited during phosphate deprivation.
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PMID:Adaptation to phosphate deprivation in osteoblast-like cells. 832 80

Bordetella avium is the etiological agent of an upper respiratory disease in birds which, symptomatically and pathologically, resembles bordetellosis in humans. Studies of the virulence of this organism revealed a novel cytotoxic protein, designated osteotoxin, that was lethal for MC3T3-E1 osteogenic cells, fetal bovine trabecular cells, UMR106-01(BSP) rat osteosarcoma cells, and embryonic bovine tracheal cells. The osteotoxin lacked dermonecrotic toxin activity, exhibited no cross-reactivity with antibody against B. avium dermonecrotic toxin, and was non-proteolytic. Osteotoxin (M(r) approximately 80,000 by gel filtration, pI 5.4) was purified to electrophoretic homogeneity from B. avium 197. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and spectrophotometric analyses showed that the native protein was a homodimer and that each of the non-covalently linked subunits (M(r) approximately 41,000) contained one molecule of pyridoxal 5'-phosphate. Microsequencing of the first 32 amino acids from the NH2 terminus allowed the synthesis of two oligonucleotide probes, which, together with polyclonal antibody to the purified protein, facilitated cloning, sequencing, and expression of the osteotoxin gene product in Escherichia coli. The open reading frame encodes a polypeptide of 396 amino acid residues (M(r) = 42,606, calculated pI 5.9), whose sequence exhibits approximately 38% identity (approximately 60% similarity) to pyridoxal 5'-phosphate-dependent beta-cystathionase(s) from E. coli, Salmonella typhimurium, and rat liver. The characteristic motif, TKYXXGHSD, associated with binding the cofactor in these enzymes is also present in osteotoxin. Physicochemical and enzymatic analyses established the coidentity of osteotoxin with beta-cystathionase. The region upstream of the beta-cystathionase (metC) gene in B. avium 197 lacked regulatory sequences ("Met boxes") described for metC in enteric species, and enzyme production was not repressed by methionine. Incubation of MC3T3-E1 osteogenic cells in medium containing L-[35S]cystine and purified beta-cystathionase resulted in 35S-labeling of the enzyme and at least one major MC3T3-E1 cell protein (M(r) approximately 50,000). cytotoxicity can be attributed to: 1) beta-cystathionase-catalyzed cleavage of L-cystine in the medium and formation of reactive sulfane-containing derivative(s), and 2) transfer of sulfane sulfur to metabolically sensitive or structurally important proteins in the osteogenic cells.
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PMID:Toxicity of Bordetella avium beta-cystathionase toward MC3T3-E1 osteogenic cells. 846 65

Inorganic phosphate (P(i)) can regulate the level of skeletal alkaline phosphatase (ALP) activity in human osteoblast-like cells, but not by means of changes in transcription or release from the cell surface. The current studies were intended to determine whether (1) P(i) affected the inactivation of ALP activity in human osteosarcoma (SaOS-2) cells; and (2) P(i)-dependent changes in ALP-specific activity were associated with equal, concomitant changes in the level of ALP immunoreactive protein. The results of these studies revealed that P(i) increased the stability of skeletal ALP activity without equivalent effects on the level of ALP immunoreactive protein. An increase in P(i) (from 0 to 1.8 mmol/liter) caused a time-dependent increase in the amount of skeletal ALP activity in the SaOS-2 cells, without a parallel increase in the amount of skeletal ALP immunoreactive protein, and a decrease in P(i) (from 1.8 to 0 mmol/liter) caused a time-dependent decrease in the amount of ALP activity, without a significant decrease in the total cellular content of ALP immunoreactive protein. Together, these observations suggest that P(i) may alter the level of skeletal ALP activity in SaOS-2 cells by inhibiting a process of irreversible inactivation that does not effect equal, concomitant changes in the level of skeletal ALP immunoreactive protein.
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PMID:Phosphate regulates the stability of skeletal alkaline phosphatase activity in human osteosarcoma (SaOS-2) cells without equivalent effects on the level of skeletal alkaline phosphatase immunoreactive protein. 856

Bone marrow stem cells reside in close proximity to endosteal osteoblasts. To explore the potential role of osteoblasts in hematopoietic differentiation, we measured the mRNA accumulation, protein production, and secretion of hematopoietic growth factors by the nonmineralizing MG-63 and the mineralizing SaOS-2 human osteosarcoma cell lines. mRNA for the osteoblast-specific protein osteocalcin was well as granulocyte colony-stimulating factor (G-CSF), transforming growth factor-beta 1 (TGF-beta 1), and tumor necrosis factor-alpha (TNF-alpha) was produced by the MG-63 and SaOS-2 cells, like primary human cells, in the presence and absence of L-ascorbate and beta-glycerol phosphate. In contrast, both cell lines expressed c-kit ligand mRNA only in the absence of L-ascorbate and beta-glycerol phosphate induction. Granulocyte-macrophage (GM)-CSF and interleukin-6 (IL-6) mRNA appeared to develop with increasing culture age. G-CSF protein was identified in several cell-associated forms including the 28- and 32-kD species, In addition, GM-CSF was found in cell-associated form. These results suggest that osteoblasts might play a central role in the hematopoietic microenvironment as basal producers of G-CSF and GM-CSF and suggest the possibility that osteoblasts may locally present these proteins in an membrane-associated fashion
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PMID:Human osteosarcoma cell lines MG-63 and SaOS-2 produce G-CSF and GM-CSF: identification and partial characterization of cell-associated isoforms. 860

In this review the effects of growth hormone (GH) on phosphocalcium homeostasis and bone metabolism are reported. Some in vitro effects of GH on chondrocytes and osteoblasts are discussed too. The main GH effects on phosphocalcium homeostasis are the permissive action on renal 1 alpha-hydroxylase activity by the hypophosphatemic stimulus and the antiphosphaturic effect by the stimulation of the maximum rate of renal tubular reabsorption of phosphate. On bone, GH is able to stimulate bone turnover and to increase bone mass. In addition, GH stimulates type I and type III collagen metabolism. In vitro, GH increases the proliferation of chondrocytes from the human growing cartilage together with the levels of interleukin-6 in the supernatant. The hormone increases also the proliferation of the human osteosarcoma-derived osteoblast-like cells and augments the osteocalcin levels in the supernatant. Thus, GH markedly influences phosphocalcium homeostasis and bone metabolism in childhood and adolescence. In addition, it is possible that GH continues to play a role in bone physiology during adulthood when final height is reached.
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PMID:Effects of growth hormone on phosphocalcium homeostasis and bone metabolism. 871 42


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