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)

We have previously shown that osteocalcin synthesis is readily induced by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in MG-63 human osteosarcoma cells (Mahonen et al. (1990) Biochim. Biophys. Acta 1048, 30-37). In the present study, the regulation of osteocalcin synthesis by other hormones of the steroid-thyroid hormone family (retinoic acid, 17 beta-estradiol, triiodothyronine, and dexamethasone) was examined. We found that the other hormones alone had no effects on medium osteocalcin and osteocalcin mRNA concentrations by 96 h of treatment. Compared with 1,25(OH)2D3, however, the combination of 1,25(OH)2D3 with dexamethasone resulted in a greatly reduced medium osteocalcin concentration. Also estradiol and triiodothyronine diminished the stimulatory effect of 1,25(OH)2D3. In contrast, the combination of 1,25(OH)2D3 with retinoic acid resulted in an increased medium osteocalcin concentration. The inhibition of osteocalcin synthesis by dexamethasone and triiodothyronine was accompanied by decreased osteocalcin mRNA levels. Retinoic acid and estradiol, however, did not influence the 1,25(OH)2D3-induced osteocalcin mRNA levels. To examine the specificity of the hormonal effects, the activity of alkaline phosphatase was determined. Both baseline and 1,25(OH)2D3-stimulated alkaline phosphatase activity was found to be inhibited by all other hormones. These results suggest that the steroidal hormones specifically affect osteocalcin synthesis in osteoblastic bone cells, and that complex interactions occur at the level of transcription and/or translation resulting in each case in a finely adjusted rate of osteocalcin synthesis.
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PMID:Modulation of 1,25(OH)2D3-induced osteocalcin synthesis in human osteosarcoma cells by other steroidal hormones. 182 Sep 70

The heterologous regulation of hormone receptors is well described in the hormone receptor literature. We were interested in determining whether human 1,25-dihydroxyvitamin D-3 receptor (hVDR) and glucocorticoid receptor (GR), members of the steroid/thyroid hormone receptor family, are heterologously regulated by other steroids and related hormones. We used human osteosarcoma cells (MG-63) and measured hVDR and GR mRNA levels after androgen, estrogen, glucocorticoid, progesterone, thyroid hormone, vitamin A and vitamin D treatments. Each hormone, except androgen and progesterone, was capable of increasing hVDR mRNA levels like the natural ligand in human osteosarcoma cells. On the other hand, GR gene expression was not affected by these hormones. To study whether the cells responded to the 1,25(OH)2D3-treatment with changes in differentiation and proliferation, we also studied c-myc and c-fos gene expression. Both genes were only regulated by 1,25(OH)2D3. 1,25(OH)2D3 slightly increased the accumulation of c-fos mRNA within 4-12 h from the hormone addition, while the increase in c-myc mRNA appeared at 24 h.
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PMID:Homologous and heterologous regulation of 1,25-dihydroxyvitamin D-3 receptor mRNA levels in human osteosarcoma cells. 184 64

In order to elucidate the mechanism of increased alkaline phosphatase (AI-P) activity of bone origin in serum of patients with hyperthyroidism, the effects of thyroid hormone on mouse osteoblast-like cells (MC3T3-E1) were studied in vitro. Triiodo-L-thyronine (T3) and thyroxine (T4) produced a dose-dependent increase in AI-P activity in the cells at minimum concentrations of 10(-10)M T3 (free T3, 5 x 10(-12) M) and 10(-8) M T4 (free T4, 8 x 10(-11) M), respectively. Scatchard analysis revealed that MC3T3-E1 cells contained nuclear binding sites specific for T3 with an apparent Kd of 120 pM (maximum number of binding sites, approximately 2500 per cell). When cells were cultured with T3 in alpha-minimal essential medium (alpha-MEM) for a prolonged period, AI-P activity also became detectable in the conditioned medium. In contrast to rat osteosarcoma cells (ROS 17/2.8), MC3T3-E1 cell growth was inhibited by T4 in a concentration-dependent manner. These findings suggest that thyroid hormone inhibits proliferation and stimulates differentiation of mouse osteoblast-like cells. Since T3 and T4 stimulate AI-P activity not only in the cells but also in the medium, we speculate that the hyper-alkaline phosphatasia frequently seen in patients with hyperthyroid Graves' disease is partly due to a direct effect of thyroid hormone on osteoblasts or osteoblast-like cells.
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PMID:Stimulation of alkaline phosphatase activity by thyroid hormone in mouse osteoblast-like cells (MC3T3-E1): a possible mechanism of hyperalkaline phosphatasia in hyperthyroidism. 319 Dec 90

The 9-cis retinoic acid receptor (RXR) alpha, a co-regulator of the thyroid hormone and vitamin D receptors, has previously been shown to be expressed predominantly in metabolic organs such as the liver and the kidney. In this study we have used a reverse transcription polymerase chain reaction (RT-PCR) to examine the expression of retinoic acid (RA) nuclear receptors in primary human osteoblasts and in SaOS-2, a human osteosarcoma-derived cell line with osteoblastic characteristics. Our results demonstrate that human osteoblasts express RXR alpha, as well as the all-trans RA receptors (RAR) alpha, beta, and gamma. These data further establish bone as a major target for retinoids and suggest that RA can regulate vitamin D and thyroid hormone actions in osteoblasts.
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PMID:Reverse transcription-polymerase chain reaction assay demonstrates that the 9-cis retinoic acid receptor alpha is expressed in human osteoblasts. 768 68

Fetal thyroid hormone (RT3) is considered metabolically inactive and is present in high concentration in fetuses and in some patients with end-stage malignant disease. In a virus-induced erythroleukemia cell model, RT3 was found to stimulate the growth of the erythroleukemia cells in culture. The focus of this research was to test the effect of RT3, at several concentrations, on the growth of naturally occurring human sarcomas in cell culture. Cloned cell lines of Ewing sarcoma, rhabdomyosarcoma, and osteogenic sarcoma were grown in multiple flasks of serum-free medium containing varying concentrations of RT3, ranging from 10(-8)-10(-5) M. Cells grown in serum-free medium containing no RT3 were used as a control. RT3 significantly increased the growth (total protein) of the rhabdomyosarcoma cell line in culture at concentrations between 10(-8) and 10(-6) M, with the maximum effect at 10(-7) M. The growth of one cell line of Ewing sarcoma was not affected by RT3 for any of the concentrations tested. The growth of two Ewing sarcomas and one osteogenic sarcoma was significantly stimulated by RT3 but only at the highest concentration of 10(-5) M. The growth of the other osteogenic sarcoma cell line was significantly increased at concentrations of 10(-6) and 10(-7) M. The stimulatory effect of RT3 on several sarcoma cell lines in culture suggests the presence of a specific receptor in the neoplastic cells and the possibility that RT3 may be useful as a model for new chemotherapeutic agents.
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PMID:Effect of fetal thyroid hormone (RT3) on sarcoma cells in culture. 832 44

The 9,000 Mr calcium-binding protein calbindin-D9k (CaBP9k) is markedly induced by 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in mammalian intestine. However, although a vitamin D response element (VDRE) has been reported in the promoter of the rat CaBP9k gene (at -490/-472), the CaBP9k promoter is weakly transactivated by 1,25-(OH)2D3. Previous studies indicated that when MCF-7 cells are transfected with the rat CaBP9k VDRE ligated to the thymidine kinase promoter and treated with both 1,25-(OH)2D3 and T3 there is an enhancement of the response observed with 1,25-(OH)2D3 alone, suggesting direct cross-talk between thyroid hormone and the vitamin D endocrine system and activation via the formation of vitamin D receptor (VDR)-thyroid hormone receptor (TR) heterodimers. To determine whether the weak response of the rat CaBP9k natural promoter to 1,25-(OH)2D3 could be enhanced by T3, CaBP9k promoter/reporter chloramphenicol acetyltransferase constructs were transfected in MCF-7 cells, and the cells were treated with the two hormones alone or in combination. No induction with T3 alone and no enhancement of reporter activity in the presence of both hormones was observed. To determine whether a lack of effect by T3 was specific for the CaBP9k promoter and to further examine the possibility of cross-talk between the TR- and VDR-signaling pathways, the 1,25-(OH)2D3-responsive rat 24 hydroxylase [24(OH)ase] promoter and the rat osteocalcin VDRE (-457/-430), both fused to reporter genes were similarly examined in MCF-7 cells. Again, no enhancement of the response to 1,25-(OH)2D3 was observed in the presence of T3. In addition, a similar lack of response to T3 but responsiveness to 1,25-(OH)2D3 was observed when UMR106-01 osteosarcoma cells [which, like MCF-7 cells, express VDR, TR, and the retinoid X receptor (RXR) endogenously] were transfected with a 1,25-(OH)2D3 responsive mouse osteopontin promoter reporter. In vitro DNA binding assays were carried out using purified human VDR, human RXRalpha, and chick T3Ralpha and 24(OH)ase, osteocalcin, osteopontin, and CaBP9k VDRE oligonucleotide probes. No VDR-TR heterodimer binding on any of these VDREs was observed, although, as expected, there was binding by the VDR-RXR complex and strong TR-RXR binding to a consensus thyroid hormone response element. Simultaneous gel retardation assays using similar and lower concentrations of TR with RXR showed strong binding of TR-RXR on a 32P-labeled thyroid response element. Studies using the yeast two-hybrid system also did not provide evidence for the formation of a VDR-TR protein-protein interaction. In addition, in vivo data showed that transfection of TR, in fact, repressed VDR-mediated transcription and that the repression could be reversed by the addition of RXR. Thus, in vitro and in vivo experiments do not support ligand-sensitive transactivation mediated by VDR-TR heterodimer formation but rather suggest that TR expression can repress 1,25-(OH)2D3-induced transcription predominantly by sequestering RXR.
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PMID:Thyroid hormone receptor does not heterodimerize with the vitamin D receptor but represses vitamin D receptor-mediated transactivation. 973 5

Thyroid hormones influence both bone formation and bone resorption. In vitro studies demonstrate direct effects of thyroid hormones on cells of the osteoblast lineage. Transcriptional regulation by thyroid hormones is mediated by ligand-dependent transcription factors called TRs. The three main T(3)-binding TR isoforms are TRalpha1, TRbeta1, and TRbeta2. TRs have been identified in cells of the osteoblast lineage, but it is still not known whether TR isoform expression differs in primary cultures of human osteoblasts. We used immunocytochemistry, Western blotting, nuclear binding assays, and transient transfection studies to examine the expression of functional TR isoforms in primary cultures of osteoblasts (hOb) derived from explants of trabecular bone, in human bone marrow stromal cells (hBMS), which are believed to be the source of osteoblast progenitor cells, and for comparison in the transformed human osteosarcoma cell lines MG63 and SaOs-2. TRalpha1, TRbeta1, and TRbeta2 proteins were expressed in all cells, although expression was greatest in MG63 > hBMS > SaOs-2 > hOb. Differences between isoforms were also apparent, with TRalpha1> TRbeta1 > TRbeta2 in all cell types. Incubation with [(125)I]T(3) confirmed reversible T(3) binding to cell nuclei. Specific binding was greatest in MG63 > hBMS > SaOs-2 > hOb. Finally, endogenous TR activity was determined in transfections using a thyroid hormone response element derived from the rat GH gene linked to the luciferase reporter gene. In MG63 and hBMS cells T(3) treatment increased luciferase activity 5.5 +/- 0.7-fold (P < 0.05), confirming the presence of endogenous receptors. In SaOs-2 and hOb cells, T(3) treatment had no effect on thyroid hormone response element-thymidine kinase-luciferase expression, suggesting that in these cells TR expression was too low to be detected. These results indicate that three main TR isoforms are expressed in cells of the human osteoblast lineage, but that expression and endogenous TR activity are predominantly present in hBMS cells. Whether there are distinct mechanisms of thyroid hormone action mediated by TRalpha1, TRbeta1, and TRbeta2 in hOb and hBMS cells remains to be shown.
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PMID:TR expression and function in human bone marrow stromal and osteoblast-like cells. 1183 40

Bone tumor incidence in women peaks at age 50-60, coinciding with the menopause. That estrogen (E2) and triiodothyronine (T3) interact in bone metabolism has been well established. However, few data on the action of these hormones are available. Our purpose was to determine the role of E2 and T3 in the expression of bone activity markers, namely alkaline phosphatase (AP) and receptor activator of nuclear factor kappaB ligand (RANKL). Two osteosarcoma cell lines: MG-63 (which has both estrogen (ER) and thyroid hormone (TR) receptors) and SaOs-29 (ER receptors only) were treated with infraphysiological E2 associated with T3 at infraphysiological, physiological, and supraphysiological concentrations. Real-time RT-PCR was used for expression analysis. Our results show that, in MG-63 cells, infraphysiological E2 associated with supraphysiological T3 increases AP expression and decreases RANKL expression, while infraphysiological E2 associated with either physiological or supraphysiological T3 decreases both AP and RANKL expression. On the other hand, in SaOs-2 cells, the same hormone combinations had no significant effect on the markers' expression. Thus, the analysis of hormone receptors was shown to be crucial for the assessment of tumor potential growth in the face of hormonal changes. Special care should be provided to patients with T3 and E2 hormone receptors that may increase tumor growth.
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PMID:The importance of hormone receptor analysis in osteosarcoma cells growth submitted to treatment with estrogen in association with thyroid hormone. 1743 20

Antioxidants are substances that function to protect cells from damage caused by unstable free radicals and reactive oxygen species (ROS). These agents are also quite successful in deterring certain disease processes specifically, cancer. Antioxidants help fight these excess free radicals or ROS by donating electrons to make a more stable chemical group. Thymoquinone (TQ) is a major active component of black seed (Nigella sativa) and has been used in the Middle East for centuries to treat disease processes. Selenium (Se), unlike TQ, is found in almost all human tissue and is classified as a trace element. Se has the ability to modify cells by acting as antioxidants, modifying redox status and thyroid hormone metabolism. The purpose of this study was to further examine the use of TQ, an extra-cellular anti-oxidant, and Se, an endogenous antioxidant on the proliferation of osteoblasts cells (MG 63) in tissue culture. MG 63 cells were treated with conventional low, medium and high doses of TQ and Se to obtain an optimal dose for combined treatment. Results and biochemical markers were evaluated at 24, 48 and 72 hours for all groups. The combined dose of TQ and Se produced decreased cell counts, increased cellular damage, decreased alkaline phosphatase levels, and decreased glutathione levels as compared to control (P>0.05). These results indicate that the combined use of TQ and Se may be an effective treatment option against human osteosarcoma cells.
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PMID:Effects of thymoquinone and selenium on the proliferation of mg 63 cells in tissue culture. 1914 54

Osteosarcoma is the most common primary high-grade bone tumor in both adolescents and children. Early tumor detection is key to ensuring effective treatment. Serum marker discovery and validation for pediatric osteosarcoma has accelerated in recent years, coincident with an evolving understanding of molecules and their complex interactions, and the compelling need for improved pediatric osteosarcoma outcome measures in clinical trials. This review gives a short overview of serological markers for pediatric osteosarcoma, and highlights advances in pediatric osteosarcoma-related marker research within the past year. Studies in the past year involving serum markers in patients with pediatric osteosarcoma can be assigned to one of four categories, i.e., new approaches and new markers, exploratory studies in specialized disease subsets, large cross-sectional validation studies, and longitudinal studies, with and without an intervention.Most of the studies have examined the association of a serum marker with some aspect of the natural history of pediatric osteosarcoma. As illustrated by the many studies reviewed, several serum markers are emerging that show a credible association with disease modification. The expanding pool of informative osteosarcoma-related markers is expected to impact development of therapeutics for pediatric osteosarcoma positively and, it is hoped, ultimately clinical care. Combinations of serum markers of natural immunity, thyroid hormone homeostasis, and bone tumorigenesis may be undertaken together in patients with pediatric osteosarcoma. These serum markers in combination may do better. The potential effect of an intrinsic dynamic balance of tumor angiogenesis residing within a single hormone (tri-iodothyronine) is an attractive concept for regulation of vascularization in pediatric osteosarcoma.
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PMID:Serum tumor markers in pediatric osteosarcoma: a summary review. 2258 2


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