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)

Altered carbohydrate metabolism associated with fibrosarcomas and chondrosarcomas has been well-documented in past literature. This report describes abnormal carbohydrate metabolism in 2 osteosarcoma patients, and abnormalities in growth hormone and somatomedin serum levels. Experimental evidence is presented showing in vitro suppression of osteosarcoma tumor cell proliferation by 17 beta Estradiol. Estrogen inhibition of linear bone growth, cartilage proliferation, and somatomedin is discussed with reference to possible estrogen therapy in osteosarcoma.
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PMID:Investigation of carbohydrate metabolism and somatomedin in osteosarcoma patients. 105 23

In this immunocytochemical study we have probed a number of human bone cell types and bone preparations for the presence of the estrogen receptor (ER) with two distinct monoclonal antibodies. Using a well-validated antibody (H222) that recognizes human ER and standard peroxidase-antiperoxidase methodology, we were unable to demonstrate nuclear staining for ER in cultured primary or transformed human bone-derived cells or in fetal bone sections. Attempts to visualize ER in osteosarcoma cell lines (TE85C and HTB96) using a silver enhancement procedure were also unsuccessful. Additionally, we failed to detect immunocytochemical staining for the progesterone receptor (using monoclonal antibody mPR1) in control or estrogen-treated human bone cell cultures. Estrogen and progesterone receptor staining was readily detectable in MCF7 human breast cancer cells. In contrast, with a monoclonal antibody that recognizes a 29 kDa cytoplasmic component (p29) closely related to human ER, we observed specific staining in all the osteoblastlike cells studied. Cytoplasmic staining for this p29 antigen was most intense in primary cultures of human bone-derived cells. It is possible that the relatively abundant but as yet undefined p29 antigen may act as a sensitive marker for the presence of ER in cells at levels below the detection limit of the anti-ER monoclonal antibody. If so, our results are consistent with the presence of ER in osteoblastlike cells at very low concentrations.
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PMID:Estrogen receptors and human bone cells: immunocytochemical studies. 247 30

Postmenopausal women lose bone mineral density and this loss can be prevented by estrogen administration. Although the skeletal effects of estrogens have been regarded previously as indirect, estrogen receptors have been discovered in cultured human osteoblasts and related cell lines. The UMR106 cell line derived from a rat osteogenic osteosarcoma is such an osteoblast model. We have shown direct effects of estradiol (E) on these cells in vitro, inhibiting growth and stimulating alkaline phosphatase activity (AP) corrected for cell number. This response was maximal at E conc. of 10(-10) M in serum and Phenol Red free medium, was metabolite specific and cell cycle-dependent. These cells contain high affinity binding sites with a Kd of 0.5 nM. Estrogen receptors were detected by the monoclonal antibody H-222 on Western blot after initial immunoprecipitation to concentrate the proteins. E treatment increased several enzymes including creatine kinase and LDH isoenzymes along with increments in intracellular transferrin. Transforming growth factor-beta is secreted by these cells. Secretion of this peptide was stimulated by E. TGF-beta mediated the transient growth inhibition associated with E treatment. Insulin like growth factors (IGF) are also secreted by these cells with IGF-II concentrations in the culture medium being eight times higher than IGF-I levels. E treatment increased the concentrations of both IGFs in the culture medium after a 3 day incubation. Exposure of E treated cells manifested a mitogenic response and reduced AP, indicating that E induced receptors for IGFs. These findings establish direct effects of E on osteoblastic cells in vitro and demonstrate responses to E at many levels. These osteoblast responses in vitro suggest an important role for sex steroids in the development and function of the osteoblast lineage.
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PMID:Estrogens and the skeleton: cellular and molecular mechanisms. 262 18

Estrogen depletion causes postmenopausal osteoporosis. Here we report that steady state mRNA levels of transforming growth factor-beta 1 (TGF-beta 1) and osteocalcin in bone persistently decreased and increased, respectively, in vivo in estrogen-depleted rats after ovariectomy (OVX). 21 female Wistar rats (7-month-old) were randomized and underwent OVX or sham-operation, total RNA was extracted from tibiae and assessed by Northern blot analysis. OVX induced 70-80% decrease in TGF-beta 1 mRNA levels and 2- to 3-fold increase in mRNA levels of osteocalcin compared with controls three weeks after surgery. These changes persisted up to twelve weeks post-operation. OVX caused 15% reduction in femoral bone mineral density and 2-fold elevation in serum osteocalcin levels as early as two weeks post-operation. Moreover, estrogen depletion resulted in marked decrease and increase, respectively, in steady state mRNA levels of TGF-beta 1 and osteocalcin in vitro in osteoblastic rat osteosarcoma cells, ROS 17/2.8. Our results provide the first in vivo evidence that expression of TGF-beta and osteocalcin in bone is reciprocally regulated at the transcriptional level in estrogen deficient OVX rats and suggests that TGF-beta 1 may play a role in estrogen-dependent maintenance of normal bone density.
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PMID:Ovariectomy decreases the mRNA levels of transforming growth factor-beta 1 and increases the mRNA levels of osteocalcin in rat bone in vivo. 835 80

Bone is an estradiol-responsive tissue. Estrogen withdrawal during the menopause causes loss of bone mass and clinically relevant osteoporosis in a third of all women. Sufficient or impaired local production, as well as degradation of estradiol in cells present in the bone microenvironment might be an important mechanism of rescue or might contribute to the development of osteoporosis, respectively. We therefore investigated aromatase and 17beta-hydroxysteroid dehydrogenase type IV (17beta-HSD IV) expression in osteoblast- and osteoclast-like cells. Aromatase mRNA was increasingly expressed in myeloid THP 1 cells differentiated along the monocyte/phagocyte pathway exploiting vitamin D and either granulocyte-macrophage-stimulating factor (GMCSF) or macrophage-stimulating factor (MCSF). In long-term cultures, when sequentially exposed to vitamin D (days 0-21) and GMCSF (days 5-10) and plated on collagen, the amount of expression of aromatase mRNA steadily increased along with the increasing expression of osteopontin mRNA, alpha(v) integrin mRNA, c-fms (MCSF-receptor) mRNA and multinucleated cells developing. The conversion of estradiol from testosterone (10(-7) M/l) in the supernatants of dishes mirrored changes in aromatase mRNA expression and by day 21 rose to 30,000 ng/10(7) cells/24 h. 17Beta-HSD IV mRNA expression was abundant in undifferentiated THP 1 cells and was decreased to approximately 50% by day 21. Unstimulated SV-40 immortalized fetal osteoblasts did not express aromatase mRNA, but the expression was stimulated by the addition of the phorbol ester phorbol myristate acetate (PMA). Unstimulated osteoblasts from primary cultures did not express aromatase mRNA. Osteoblast-like osteosarcoma cells MG 63 expressed faint levels of aromatase mRNA in contrast to the osteosarcoma cell line HOS 58. 17Beta-HSD IV mRNA was expressed in fetal osteoblasts as well as in osteoblasts from primary culture, MG 63 and HOS 58 cells. In summary, we can show the expression of estradiol metabolizing enzymes in cells which are present in the bone microenvironment. Impaired aromatase expression and/or enhanced expression of 17beta-HSD IV may contribute to the pathogenesis of osteoporosis.
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PMID:Local estradiol metabolism in osteoblast- and osteoclast-like cells. 936 87

Estrogen sulfatase and sulfotransferase (EST) activities are present in breast cancer tissues but there are no reports on EST in cancerous bone cells. We incubated [(3)H]estradiol-17beta with cells from a canine osteosarcoma D17 line for periods up to 24 h. Radioactive steroids were recovered from the media and separated into unconjugated and conjugated fractions using Sep-Pak C18 cartridges. The conjugate fraction was solvolyzed and the resulting free steroids were obtained from a second C18 cartridge. Little metabolism was apparent in 4 h of incubation, but by 24 h as much as one half of the radioactivity was seen in the conjugate fraction. Most of the conjugates were recovered as sulfates in all three experiments. HPLC profiles showed a limited metabolism of estradiol to other compounds except for estrone, which was clearly present in both free and sulfate fractions. These results suggest that EST may have a role in the local metabolism of estrogens in bone.
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PMID:Estradiol-17beta sulfotransferase activity in canine osteosarcoma D17 cells. 1087 35

Estrogen (17beta-estradiol, E2) plays pivotal roles in the function and maintenance of the skeleton, including the bone-forming osteoblasts (OBs). The functions of E2 are largely mediated through two distinct estrogen receptor isoforms, ERalpha and ERbeta, both of which are expressed in OBs. The level of each isoform dominates at early or late stages of OB differentiation. To date, only a limited comparison between the transcriptional targets of ERalpha and ERbeta on endogenous gene expression has been reported. We have developed new stable cell lines, which contain doxycycline (Dox)-inducible ERalpha and ERbeta, in the U2OS human osteosarcoma to determine the global transcriptional profile of ERalpha- and ERbeta-regulation of endogenous gene expression. The U2OS-ERalpha and U2OS-ERbeta cell lines were treated with Dox and either vehicle control or E2 for 24 h. Gene expression analysis was performed using a microarray containing approximately 6,800 full-length genes. We detected 63 genes that were regulated solely by ERalpha and 59 genes that were only regulated solely by ERbeta. Of the ERalpha-regulated genes, 81% were upregulated and 19% were inhibited. Similarly 76% of the ERbeta-regulated genes were upregulated whereas 24% were inhibited by E2. Surprisingly, only 17 genes were induced by both ERalpha and ERbeta. Real-time PCR was employed to confirm the expression of a selected number of genes. The regulation of a number of known E2-responsive genes in human OBs, as well as many interesting novel genes, is shown. The distinct patterns of E2-dependent gene regulation in the U2OS cells by ERalpha and ERbeta shown here suggest that during OB differentiation, when either isoform dominates, a unique pattern of gene responses will occur, partially due to the differentiation state and the ER isoform present.
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PMID:Estrogen receptor isoform-specific regulation of endogenous gene expression in human osteoblastic cell lines expressing either ERalpha or ERbeta. 1450 48

Estrone sulfate (E1S) is the most abundant estrogen in the circulation of adults. The present study was undertaken to assess estrone (E1) and estradiol formation from E1S in freshly resected bone [bone fragments (BFs)] and osteoblast-like cells (hOB) cultured from BFs. Furthermore, we compared estrogen formation from E1S in rat and human osteosarcoma (OS) cell lines and that of estrogen formation from E1S with that of aromatization of androstenedione and testosterone in BFs and those from E1S and androstenedione in hOB cells. The bone used was from the head of the femur from a total of 15 women and 12 men. Steroid sulfatase activity (STA) was found, and the formation of estrone and estradiol from E1S was demonstrated. STA was similar in cells derived from BFs of men and women. STA was significantly lower in OS cell lines, compared with hOB cells. Estrogen formation from E1S in BFs was at least 20 times higher than that from androstenedione and about 50 times higher than that from testosterone. Similarly, estrogen formation from E1S in hOB cells exceeded the values derived from aromatization of androstenedione by two orders of magnitude. Based on these results, we conclude that hOB cells express the same pattern of E1S metabolism as resected bone and thus may accurately mirror the in vivo situation in man. In comparison with hOB cells, STA is fundamentally lower in widely used OS cell lines that express an osteoblastic phenotype. This shortcoming precludes their use as model cell lines to unravel STA metabolic pathways and its regulation in nontumorous bone. E1S is a major source of local bioactive estrogen formation in human bone. Because bone is highly susceptible to estrogen action, local estrogen formation from E1S may play an important role in bone maturation and homeostasis, particularly in elderly adults.
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PMID:Estrone sulfate is a major source of local estrogen formation in human bone. 1535 81

Estrogen receptors (ERs) stimulate genomic effects by acting as nuclear transcription factors as well as non-genomic effects by activating distinct cytoplasmic protein kinase cascades. Non-genomic effects have been implicated in numerous cellular processes, such as proliferation, differentiation, apoptosis and vasorelaxation. To exploit non-genomic effects mediated by ERalpha for novel hormone replacement regimens, we screened a focused library of steroid receptor ligands to identify compounds exhibiting properties different from estradiol, i.e. substances that selectively stimulate non-genomic signal transduction pathways while exhibiting low genomic activities. Treatment of breast cancer cells and osteosarcoma cells with estradiol, estren, substance A and substance B led to non-genomic activation of Akt (protein kinase B) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling cascades mediated by Src (Rous Sarcoma Virus, non-receptor tyrosine kinase) and phosphatidylinositol-3-kinase (PI3K) stimulation. Such compounds leading to prominent Akt/ERK activation but exhibiting only weak genomic properties were applied in vasorelaxation assays, modeling physiological non-genomic ER responses. As expected from PI3K and Src activation data, substances were as effective as estradiol in mediating vasorelaxation. We assume that these pathway-selective estrogen receptor ligands may serve as potent lead structures for novel hormone replacement strategies exhibiting lesser side effects than the existing treatment paradigms.
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PMID:Identification of estrogen receptor ligands leading to activation of non-genomic signaling pathways while exhibiting only weak transcriptional activity. 1620 30

Estrogen receptors alpha (ERalpha) and beta (ERbeta) have distinct functions and differential expression in certain tissues. These differences have stimulated the search for subtype-selective ligands. Therapeutically, such ligands offer the potential to target specific tissues or pathways regulated by one receptor subtype without affecting the other. As reagents, they can be utilized to probe the physiological functions of the ER subtypes to provide information complementary to that obtained from knock-out animals. A fluorescence resonance energy transfer-based assay was used to screen a 10,000-compound chemical library for ER agonists. From the screen, we identified a family of ERbeta-selective agonists whose members contain bulky oxabicyclic scaffolds in place of the planar scaffolds common to most ER ligands. These agonists are 10-50-fold selective for ERbeta in competitive binding assays and up to 60-fold selective in transactivation assays. The weak uterotrophic activity of these ligands in immature rats and their ability to stimulate expression of an ERbeta regulated gene in human U2OS osteosarcoma cells provides more physiological evidence of their ERbeta-selective nature. To provide insight into the molecular mechanisms of their activity and selectivity, we determined the crystal structures of the ERalpha ligand-binding domain (LBD) and a peptide from the glucocorticoid receptor-interacting protein 1 (GRIP1) coactivator complexed with the ligands OBCP-3M, OBCP-2M, and OBCP-1M. These structures illustrate how the bicyclic scaffolds of these ligands are accommodated in the flexible ligand-binding pocket of ER. A comparison of these structures with existing ER structures suggests that the ERbeta selectivity of OBCP ligands can be attributed to a combination of their interactions with Met-336 in ERbeta and Met-421 in ERalpha. These bicyclic ligands show promise as lead compounds that can target ERbeta. In addition, our understanding of the molecular determinants of their subtype selectivity provides a useful starting point for developing other ER modulators belonging to this relatively new structural class.
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PMID:Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity. 1664 39


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