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)

Using routinely processed, paraffin-embedded tissue specimens, osteoclast-like giant cells in giant cell tumour of bone (GCT), chondroblastoma, osteoblastoma and osteoblastic osteosarcoma were examined histochemically for osteoclast-specific enzymes tartrate-resistant acid phosphatase (TRAP) and carbonic anhydrase isoenzyme II (CA-II). Osteoclast-like giant cells and some mononuclear cells possessed TRAP activity. These were further classified with respect to CA-II immunoreactivity, i.e. cells with CA-II were seen in GCT and chondroblastoma, while those in osteoblastoma and osteoblastic osteosarcoma were negative for CA-II. All the cellular components in malignant fibrous histiocytoma and various extraosseous inflammatory lesions including malignant giant cells and macrophage polykaryons were negative for both TRAP and CA-II. These results indicate that osteoclast-like giant cells in GCT, chondroblastoma, osteoblastoma and osteoblastic osteosarcoma are all osteoclasts and generated by fusion of mononuclear cells with the same histochemical characteristics as osteoclast-like giant cells. The difference in CA-II immunoreactivity suggests the functional or maturational difference between osteoclast-like giant cells in GCT and chondroblastoma and those in osteoblastoma and osteosarcoma.
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PMID:Histochemistry of tartrate-resistant acid phosphatase and carbonic anhydrase isoenzyme II in osteoclast-like giant cells in bone tumours. 162 81

In osteoclastic giant cells of six different tumors of bones and joints (fibrous dysplasia, proliferating giant cell tumor, malignant giant cell tumor, osteosarcoma after chemotherapy, malignant synovioma and Ewing's sarcoma) activities of tartrate-resistant acid phosphatase, NADH-tetrazolium-oxidoreductase and, in three of them, of non-specific esterase are determined by enzyme histochemical methods. Quantitative microphotometry makes it possible to determine relative enzyme activities in the cut sections of giant cells of different sizes. Giant cells of the various tumors reveal similar trends: With an increase in cell size, mean extinctions of NADH-tetrazolium-oxidoreductase and non-specific esterase decrease. Mean extinctions of tartrate-resistant acid phosphatase increase in cells of medium size, whereas the large cells reveal in part low activities. An additional ultrastructural examination of the giant cells in the proliferating giant cell tumor as well as in the osteosarcoma shows morphological signs of degeneration in the large cells. Electron probe microanalysis of the proliferating giant cell tumor exhibits evidence of phagocytosis of Ca and/or Fe containing particles. The similar size dependent reaction pattern of enzymes in osteoclastic giant cells of different tumors favors the concept of a common histogenesis, i.e. a host reaction.
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PMID:Size dependent enzyme activities of multinucleated (osteoclastic) giant cells in bone tumors. 303 7

Insulin-like growth factor-I (IGF-I) and IGF-II have powerful, well defined effects on osteoblastic cells, stimulating their proliferation and inducing collagen synthesis, but the role of IGF-I and -II in modulating osteoclast differentiation and activity remains unclear. We first examined the bone-resorptive effects of IGF-I and IGF-II by assessing 45Ca2+ release from neonatal mouse calvarial bones. Both IGFs dose dependently stimulated bone resorption, with an EC50 of 8 x 10(-9) M for IGF-I and 2 x 10(-8) M for IGF-II. We then tested the effects of the IGFs on bone resorption by rat isolated osteoclasts cultured on ivory slices. Neither IGF-I nor IGF-II stimulated isolated osteoclast activity. However, in the presence of either primary mouse osteoblasts or human osteosarcoma MG 63 cells, both IGFs enhanced osteoclast resorptive activity, with an EC50 of 5 x 10(-10) M for IGF-I and 10(-9) M for IGF-II. Stimulation was not mediated by BALB/c/3T3 cells, a nonosteoblastic cell line. The effects of the IGFs were blocked by alpha IR-3, an antibody to the type I IGF receptor, but not by beta-galactosidase, a lysosomal enzyme that competes with IGF-II for the type II IGF receptor. We then examined the effects of the IGFs on the formation of osteoclast-like multinucleate cells (MNCs) in mouse bone marrow cultures. IGF-I and -II dose dependently increased the number of tartrate-resistant acid phosphatase (TRAP)-positive MNCs, although their effects were less than that of 1,25-dihydroxyvitamin D3 (a hormone that induces osteoclast differentiation). No TRAP-positive MNCs appeared in the absence of these hormones. Like authentic osteoclasts, the TRAP-positive MNCs formed in response to IGF-I and -II bound [125I]salmon calcitonin. When mouse bone marrow cells were cultured on ivory slices in the presence of either IGF-I or IGF-II for 10 days, numerous resorption lacunae were formed. beta-Galactosidase had no effect on IGF-mediated osteoclast formation. These results are strong evidence that both IGF-I and IGF-II stimulate bone resorption in vitro by enhancing osteoclast formation and function. Our data also suggest that the IGFs act through the intermediary of osteoblastic cells to stimulate osteoclast activity and that the type I, but not the type II, IGF receptor is involved in their responses. We propose that the local production of IGF-I and IGF-II may modulate both osteoblast-osteoclast interactions and osteoclast formation and play an important role in bone remodeling.
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PMID:Osteoblasts mediate insulin-like growth factor-I and -II stimulation of osteoclast formation and function. 782 21

Inorganic phosphate (Pi) can regulate the level of skeletal alkaline phosphatase (ALP) activity in human osteoblast-like cells by stabilizing the enzyme (without affecting transcription, ALP release from the cell surface, or the amount of ALP protein). These observations suggest that Pi determines the level of ALP activity by modulating a process of irreversible inactivation. The current studies were intended to examine the hypothesis that this inactivation of ALP activity is caused by the dissociation of an active center Zn and that Pi inhibits that dissociation. Initial studies showed that Zn, like Pi, could increase ALP specific activity in human osteosarcoma SaOS-2 cells in a time- and dose-dependent manner (e.g., a 50% increase at 0.2 micromol/liter Zn, P < 0.005). This effect was specific for Zn (i.e., no similar effect was seen with Ca, Fe, Co, Mg, Mn, or Cu), but not for SaOS-2 cells. Zn also increased ALP specific activity in (human osteosarcoma) MG-63 cells and in cells derived from normal human vertebrae (P < 0.001 for each). The effect of Zn to increase ALP activity was not associated with parallel increases in total protein synthesis, collagen production, or tartrate-resistant acid phosphatase activity (no change in any of these indices), net IGF-2 synthesis (a Zn-dependent decrease, P < 0.005), or PTH-dependent synthesis of cAMP (a biphasic increase, P < 0.02). Kinetic studies of Pi and Zn as co-effectors of ALP activity showed that Zn was a mixed-type effector with respect to Pi, whereas Pi was competitive with respect to Zn. Mechanistic studies showed that (1) Zn reversed the effect of Pi withdrawal to decrease ALP activity, but not by reactivating inactive ALP protein (the process required protein synthesis, without increases in ALP mRNA or the level of ALP immunoreactive protein); (2) Zn increased the half-life of ALP activity in intact cells and after a partial purification; and (3) Pi inhibited the process of ALP inactivation by EDTA (which chelates active center Zn). All these findings are consistent with the general hypothesis that Pi increases the half-life of skeletal ALP by preventing the dissociation of active center Zn and with a mechanistic model of skeletal ALP activity in which active center Zn participates in Pi-ester binding and/or hydrolysis.
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PMID:Effects of zinc on human skeletal alkaline phosphatase activity in vitro. 991 26

Subclones of the human osteosarcoma cell line SaOS-2 were established by transfecting with an expression vector containing the human PTH/PTH-related protein (PTHrP) receptor, and their abilities to support osteoclast-like multinucleated cell (OCL) formation were examined in coculture with mouse or human hemopoietic cells. Of four subclones examined, SaOS-2/4 and SaOS-4/3 bound high levels of [125I]-PTH and produced a significant amount of cAMP in response to PTH. OCLs were formed in response to PTH in the cocultures of mouse bone marrow cells with either SaOS-2/4 cells or SaOS-4/3 cells. Human OCLs were also formed in response to PTH in the coculture of SaOS-4/3 cells and human peripheral blood mononuclear cells. Adding dexamethasone together with PTH greatly enhanced PTH-induced human OCL formation. Like mouse OCLs, human OCLs formed in response to PTH were tartrate-resistant acid phosphatase positive, expressed abundant calcitonin receptors and vitronectin receptors, and formed resorption pits on dentine slices. Other osteotropic factors such as 1alpha,25-dihydroxyvitamin D3, prostaglandin E2, and interleukin 6 plus soluble interleukin 6 receptors failed to induce mouse and human OCLs in cocultures with SaOS-4/3 cells. Both mouse and human OCL formation supported by SaOS-4/3 cells were inhibited by either adding an antibody against macrophage-colony stimulating factor or adding granulocyte/macrophage-colony stimulating factor. Thus, it is likely that human and mouse OCL formation supported by SaOS-4/3 cells are similarly regulated. These results indicate that the target cells of PTH for inducing osteoclast formation are osteoblast/stromal cells but not osteoclast progenitor cells in the coculture. This coculture model will be useful for investigating the abnormalities ofosteoclast differentiation and function in human metabolic bone diseases.
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PMID:Human osteoclast-like cells are formed from peripheral blood mononuclear cells in a coculture with SaOS-2 cells transfected with the parathyroid hormone (PTH)/PTH-related protein receptor gene. 992 25

Osteoporosis is a serious complication of systemic glucocorticoid use. However, while glucocorticoids increase bone resorption in vitro and in vivo, the mechanism(s) of this effect are at present unclear. Recent studies have identified the osteoprotegerin (OPG) ligand (OPG-L) as the final effector of osteoclastogenesis, an action that is opposed by the soluble neutralizing receptor, OPG. Thus, we assessed glucocorticoid regulation of OPG and OPG-L in various human osteoblastic lineage cells using Northern analysis, RT-PCR, and ELISA. Dexamethasone inhibited constitutive OPG messenger RNA (mRNA) steady-state levels by 70-90% in primary (MS) and immortalized stromal cells (hMS), primary trabecular osteoblasts (hOB), immortalized fetal osteoblasts (hFOB), and osteosarcoma cells (MG-63). In hFOB cells, dexamethasone inhibited constitutive OPG mRNA steady-state levels in a dose- and time-dependent fashion by 90%, and also suppressed cytokine-stimulated OPG mRNA steady-state levels. Dexamethasone-induced inhibition of OPG mRNA levels was not affected by the protein synthesis inhibitor, cycloheximide, and was shown to be due to inhibition of OPG gene transcription using a nuclear run-on assay. Moreover, dexamethasone also dose dependently (10(-10) M-10(-7) M) inhibited constitutive OPG protein concentrations in the conditioned medium of hFOB cells from 2.59 +/- 0.02 ng/ml (control) to 0.30 +/- 0.01 ng/ml (88% inhibition; P < 0.001 by ANOVA). Concurrently, dexamethasone stimulated OPG-L mRNA steady-state levels in MS and hFOB cells by 2- and 4-fold, respectively. Treatment of murine marrow cultures with conditioned medium harvested from dexamethasone-treated MG-63 cells increased tartrate-resistant acid phosphatase (TRAP) activity by 54% (P < 0.005) compared with medium harvested from control-treated cells (in the presence of OPG-L and macrophage colony-stimulating factor). Moreover, dexamethasone (10(-8) M) promoted osteoclast formation in vitro, as assessed by a 2.5-fold increase of TRAP activity in cell lysates (P < 0.001) and the appearance of TRAP-positive multinucleated cells. Our data are thus consistent with the hypothesis that glucocorticoids promote osteoclastogenesis by inhibiting OPG and concurrently stimulating OPG-L production by osteoblastic lineage cells, thereby enhancing bone resorption.
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PMID:Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. 1049 88

The molecular mechanisms underlying Paget's disease and subsequent osteosarcoma formation are not well understood. In this study, we aim to delineate the function of the c-Fos oncogene in Paget's disease using transgenic mice, based on previous findings that c-Fos is highly expressed in Pagetic osteoclasts and that c-Fos is an essential gene for osteoclast differentiation and skeletal neoplasia. We have generated transgenic mice in which c-Fos is overexpressed specifically in osteoclasts using the tartrate-resistant acid phosphatase (TRAP) promoter, and five founder mice have been identified. All transgene-expressing animals developed severe bone remodeling lesions, some of which progressed to large bone tumors. Histopathologic analysis indicated that the lesions contained a marked increase in the number of osteoclasts that contained a large number of nuclei. Osteoclasts were identified by histochemical staining for TRAP and by in situ hybridization for matrix metalloproteinase-9 (MMP-9) expression. Moreover, transgenic osteoclasts, and in some cases, osteoblasts and chondrocytes, expressed high levels of c-Fos protein as judged by immunocytochemistry. This phenotype of increased osteoclast number and activity, together with an apparently high rate of bone turnover, resembles some characteristics of Paget's disease. These data therefore support an important function for c-Fos in the Pagetic phenotype, and further support the notion that this gene is important in osteoclastogenesis and in bone remodeling disorders.
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PMID:A putative role for c-Fos in the pathophysiology of Paget's disease. 1051 Feb 9

The antitumor effect of intra-tumoral injection of Cepharanthin, a biscoclaurin alkaloid extracted from Stephania cephalanta Hayata, and staphylococcal enterotoxin B was evaluated using F344 male rats bearing transplantable rat osteosarcoma, S-SLM. A macroscopic lung metastatic nodule of tumor was transplanted into the subcutaneous back space, and 0.5 mg of Cepharanthin and 2 pg of staphylococcal enterotoxin B were injected into the tumor on days 12, 13 and 14. On day 28, all animals were killed with an overdose of pentobarbital sodium, and the transplanted tumors and lungs were examined. The wet weight of the lungs of the rats treated with Cepharanthin and staphylococcal enterotoxin B was significantly lower, and apoptosis in the lung metastatic nodules was significantly higher than that of the control or that of rats treated with only Cepharanthin or staphylococcal enterotoxin B. In the transplanted tumors, infiltration of TRAP (tartrate-resistant acid phosphatase)-positive multinucleated giant cells was prominent in the rats treated with Cepharanthin and staphylococcal enterotoxin B. These findings indicate that intra-tumoral injection of Cepharanthin and staphylococcal enterotoxin B induced infiltration of TRAP-positive multinucleated giant cells within the transplanted rat osteosarcoma, and reduced lung metastasis.
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PMID:Prevention of lung metastasis by intra-tumoral injection of Cepharanthin and staphylococcal enterotoxin B in transplantable rat osteosarcoma. 1055 20

It is unclear how mechanical stress influences bone cells. Mechanical stress causes fluid shear stress (FSS) in the bone. Osteoblast lineage cells are thought to sense FSS and regulate bone remodeling. We therefore investigated the effects of FSS on human osteoblast-like osteosarcoma cells: SaOS-2 cells in vitro. The conditioned medium of the SaOS-2 cells after 24 h of FSS (24 h-FSS CM) showed such osteoclastic phenotype inductions as significantly increasing the number of tartrate-resistant acid phosphatase (TRAP) positive multinuclear cells in rat bone marrow cells and TRAP-positive cells in human preosteoclastic cells: FLG 29.1 cells. An enzyme-linked immunosorbent assay showed interleukin-11 (IL-11) protein to increase 7-fold in the 24 h-FSS CM. A Northern analysis showed that IL-11 mRNA increased 4-fold in the SaOS-2 cells after 6 h-FSS; however, no IL-6 mRNA expression was detected. Furthermore, the anti-human IL-11 antibody significantly neutralized the osteoclastic phenotype induction of the 24 h-FSS CM. The IL-11 mRNA up-regulation in SaOS-2 cells by the 6 h-FSS was not inhibited by the anti-human transforming growth factor-beta1 antibody, but it was significantly inhibited by indomethacin. An enzymeimmunoassay showed prostaglandin E2 to increase 7-fold in the 1 h-FSS CM. These findings thus suggest that FSS induces osteoblasts to produce IL-11 (mediated by prostaglandins) and thus stimulates bone remodeling.
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PMID:Fluid shear stress increases interleukin-11 expression in human osteoblast-like cells: its role in osteoclast induction. 1062 68

Periprosthetic osteolysis is a major cause of aseptic loosening in artificial joint replacement. It is assumed to occur in conjunction with the activation of macrophages. We have shown in vitro that human osteoblast-like cells, isolated from bone specimens obtained from patients undergoing hip replacement, phagocytose fine particles of titanium alloy (TiAlV). The human osteoblast-like cells were identified immunocytochemically by the presence of bone-specific alkaline phosphatase (BAP). With increasing duration of culture, a variable number of the osteoblastic cells became positive for the macrophage marker CD68, independent of the phagocytosis of particles, with a fine granular cytoplasmic staining which was coexpressed with BAP as revealed by immunodoublestaining. The metal particles were not toxic to the osteoblastic cells since even in culture for up to four weeks massively laden cells were vital and had a characteristic morphology. Cells of the human osteosarcoma cell line (HOS 58) were also able to phagocytose metal particles but had only a low expression of the CD68 antigen. Fluorescence-activated cell scanning confirmed our immunocytochemical results. Additionally, the cells were found to be negative for the major histocompatibility complex-II (MHC-II) which is a marker for macrophages and other antigen-presenting cells. Negative results of histochemical tests for tartrate-resistant acid phosphatase excluded the contamination by osteoclasts or macrophages in culture. Our observations suggest that the osteoblast can either change to a phagocytosing cell or that the phagocytosis is an underestimated property of the osteoblast. The detection of the CD68 antigen is insufficient to prove the monocytic lineage. In order to discriminate between macrophages and osteoblasts additional markers should be used. To our knowledge, this is the first demonstration of cells of an osteoblastic origin which have acquired a mixed phenotype of both osteoblasts and macrophages.
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PMID:Human osteoblast-like cells phagocytose metal particles and express the macrophage marker CD68 in vitro. 1075 42


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