Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of prostaglandin E(2) (PGE(2)) on the parameters for proliferation and differentiation were studied in calvarial osteoblast-like cells isolated from rats of various ages. In cells not treated with PGE(2), it was found that mineralized bone nodule (BN) formation, alkaline phosphatase (ALP) activity, and the incorporation rate of [(3)H]thymidine into the cells sharply decreased with the age of the cell donor at 6-50 weeks and then remained at a relatively constant level up to 120 weeks. Before studying the effects of PGE(2) on these parameters, we determined the change in the levels of PGE(2) produced by the untreated cells during the culture period and found that the endogenous PGE(2) reached a maximum on the 4th day of the culture, regardless of the cell donor age, followed by a sharp decrease. The endogenous production was blocked by pretreatment with a cyclooxygenase-2 (COX-2) inhibitor, NS-398, indicating the generation of PGE(2) through a COX-2 pathway. The area of BN was effectively suppressed by NS-398 in the cells from 10- to 35-week-old rats, whereas it was enhanced in the cells from 90- to 120-week-old rats. Treatment with PGE(2 )markedly increased the BN formation and the ALP activity in the cells from 4- to 35-week-old rats (defined as young rats). By contrast, PGE(2) decreased [(3)H]thymidine incorporation into the cells from young rats. The area of BN and the ALP activity decreased significantly, whereas [(3)H]thymidine incorporation into the cells increased by 60-80% in the cells of 80- to 120-week-old rats (defined as aged rats). The stimulatory effects on the cell differentiation and the inhibitory effect on the proliferation in the cells from young rats was mimicked by an EP(1) agonist, 17-phenyl-omega-trinor PGE(2), while an EP(2)/EP(4) agonist, 11-deoxy-PGE(1) and an adenylate cyclase activator, forskolin suppressed the differentiation and enhanced the proliferation regardless of the cell donor age. PGE(2), 11-deoxy-PGE(1) and forskolin, but not 17-phenyl-omega-trinor PGE(2) increased cyclic adenosine monophosphate (cAMP) production. Generation of inositol 1, 4,5-triphosphate (IP(3)) was stimulated by 17-phenyl-omega-trinor PGE(2) or PGE(2), but not by 11-deoxy-PGE(1) or forskolin increased cAMP production in the cells from young rats. By contrast, PGE(2 )had little effect on IP(3 )generation in aged rats. From the overall results, we concluded that PGE(2) exerts stimulatory and inhibitory effects on differentiation through the EP(1)-IP(3) pathway and EP(2)/EP(4)-cAMP pathway, respectively, in the cells from young rats. The EP(1)-IP(3) pathway seems to be inactive in the cells from aged rats.
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PMID:Formation of mineralized bone nodules by rat calvarial osteoblasts decreases with donor age due to a reduction in signaling through EP(1) subtype of prostaglandin E(2) receptor. 1050 94

Mutation of the adenomatous polyposis coli (APC) gene is associated with the earliest stages of colorectal tumorigenesis and appears to be responsible for the hereditary condition familial adenomatous polyposis (FAP). Evidence indicates that cyclooxygenase-2 (COX-2) is induced and at elevated levels in human colorectal cancers and in the polyps of mouse FAP models. We have used HT-29 cells, a human colorectal carcinoma cell line with a mutant carboxy-truncated APC gene, in which intact APC gene has been introduced under the control of an inducible promoter. These HT-29-APC cells provide a suitable model system to examine how COX-2 expression becomes dysregulated after loss of APC function. Induction of full-length APC causes the HT-29-APC cells to undergo apoptosis. However, differentiation, as measured by alkaline phosphatase activity, is not induced upon expression of full-length APC. Full-length APC protein has been shown to bind the intracellular protein beta-catenin and, as a result, the Lef/Tcf transcription factors are down-regulated. Analysis of APC immunoprecipitates demonstrate a time-dependent increase of beta-catenin interacting with full-length APC. Thus, the Lef/Tcf signaling pathway is intact at this point in these cells. Furthermore, upon expression of full-length APC, COX-2 protein expression is down-regulated while COX-2 mRNA levels remain the same. These data indicate that APC plays a role, either directly or indirectly, in the translational regulation of COX-2. Treatment of the HT-29-APC cells with sodium butyrate, an inducer of apoptosis, does not alter COX-2 protein expression. Thus, COX-2 down-regulation appears to be APC specific and not just due to apoptotic induction. APC appears to uniquely regulate COX-2 expression. The mechanism by which COX-2 protein expression is down-regulated in the HT-29-APC cells is under investigation.
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PMID:Introduction of full-length APC modulates cyclooxygenase-2 expression in HT-29 human colorectal carcinoma cells at the translational level. 1054 4

Previous studies suggest that the enhanced expression of the osteoblastic phenotype exhibited by MG63 osteoblast-like cells on rough Ti surfaces (R(a) 4-5 microm) involves increased production of prostaglandin. Inhibition of prostaglandin synthesis by indomethacin blocks surface-roughness-dependent decreases in cell proliferation and increases in alkaline phosphatase activity and the production of osteocalcin and TGF-beta1. This study examined the hypothesis that the increase in expression of the osteoblastic phenotype noted in MG63 cells cultured on rough Ti surfaces is mediated by inducible cyclooxygenase-2 (Cox-2) whereas Cox-1 modulates prostaglandin production and phenotypic expression of the cells under standard conditions and on smooth Ti surfaces. MG63 cells were cultured on tissue culture plastic, smooth Ti (PT, R(a) = 0.60 microm), and two rough Ti surfaces with differing morphologies (SLA, R(a) = 3.97 microm and TPS, R(a) = 5.21 microm). At 24 h after plating, media were replaced with media containing the general Cox inhibitor indomethacin (10(-7)M), the Cox-1 inhibitor resveratrol (1 or 10 microM), or the Cox-2 inhibitor NS-398 (1 or 10 microM). Media were changed again after 48 h. Five days after plating, osteocalcin, PGE(2), and TGF-beta1 content of the conditioned media were determined. Cell numbers were assessed in the same cultures used for determination of osteocalcin production. Cell layer protein and alkaline phosphatase specific activity were assessed in cultures used to measure PGE(2) and TGF-beta1. Indomethacin, resveratrol, and NS-398 had no effect on cell number. Indomethacin blocked the surface-roughness-dependent increase in PGE(2) production by up to 80%. Similarly, resveratrol inhibited up to 50% of the PGE(2) production on smooth surfaces and up to 80% on rough surfaces. In contrast, NS-398 had no effect on PGE(2) production by cells on smooth surfaces but caused a 60% reduction in cultures on rough surfaces. Indomethacin reduced alkaline phosphatase on all surfaces below basal levels. However, neither resveratrol nor NS-398 had an effect. Indomethacin blocked the stimulatory effect of surface roughness on osteocalcin production while resveratrol only partially reduced osteocalcin production, and NS398 completely blocked the surface-dependent increase. TGF-beta1 production on rough surfaces was blocked by indomethacin. The effects of resveratrol and NS-398 were dose dependent, but neither agent caused total inhibition of the increase noted on SLA, and only resveratrol blocked the increase on TPS. These results indicate that both Cox-1 and Cox-2 are involved in the response of osteoblasts to surface roughness with respect to production of PGE(2), TGF-beta1, and osteocalcin. While prostaglandin mediates the effects of surface roughness on alkaline phosphatase, neither Cox-1 nor Cox-2 appears to be involved, at least with respect to the two inhibitors used.
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PMID:Both cyclooxygenase-1 and cyclooxygenase-2 mediate osteoblast response to titanium surface roughness. 1125 88

Intracellular signals generated by mechanical strain profoundly affect the metabolic function of osteoblast-like periodontal ligament (PDL) cells, which reside between the tooth and alveolar bone. In response to applied mechanical forces, PDL cells synthesize bone-resorptive cytokines to induce bone resorption at sites exposed to compressive forces and deposit bone at sites exposed to tensile forces in an environment primed for catabolic processes. The intracellular mechanisms that regulate this bone remodeling remain unclear. Here, in an in vitro model system, we show that tensile strain is a critical determinant of PDL-cell metabolic functions. Equibiaxial tensile strain (TENS), when applied at low magnitudes, acts as a potent antagonist of interleukin (IL)-1beta actions and suppresses transcriptional regulation of multiple proinflammatory genes. This is evidenced by the fact that TENS at low magnitude: (i) inhibits recombinant human (rh)IL-1beta-dependent induction of cyclooxygenase-2 (COX-2) mRNA expression and production of prostaglandin estradiol (PGE2); (ii) inhibits rhIL-1beta-dependent induction matrix metalloproteinase-1 (MMP-1) and MMP-3 synthesis by suppressing their mRNA expression; (iii) abrogates rhIL-1beta-induced suppression of tissue inhibitor of metalloprotease-II (TIMP-II) expression; and (iv) reverses IL-1beta-dependent suppression of osteocalcin and alkaline phosphatase synthesis. Nevertheless, these actions of TENS were observed only in the presence of IL-1beta, as TENS alone failed to affect any of the aforementioned responses. The present findings are the first to show that intracellular signals generated by low-magnitude mechanical strain interfere with one or more critical step(s) in the signal transduction cascade of rhIL-1beta upstream of mRNA expression, while concurrently promoting the expression of osteogenic proteins in PDL cells.
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PMID:Signaling by mechanical strain involves transcriptional regulation of proinflammatory genes in human periodontal ligament cells in vitro. 1193 44

Chronic crystal-associated arthropathies such as gout and pseudogout can lead to local bone destruction. Because osteoblasts, which orchestrate bone remodeling via soluble factors and cell-to-cell interactions, have been described in contact with microcrystals, particularly in uratic foci of gout, we hypothesized that microcrystals of monosodium urate monohydrate (MSUM) and of calcium pyrophosphate dihydrate (CPPD) could alter osteoblastic functions. MSUM and CPPD adhered to human osteoblastic cells (hOB) in vitro and were partly phagocytized as shown by scanning electron microscopy. MSUM and CPPD dose-dependently stimulated the production of PGE(2) in hOB as assessed by enzyme immunoassay, a response that was synergistically enhanced in the presence of IL-1. The mechanism of this synergism was, at least in part, at the level of the expression of cyclooxygenase-2 as evaluated by immunoblot analysis. MSUM and CPPD also stimulated the expression of IL-6 and IL-8 and reduced the 1,25-dihydroxyvitamin D(3)-induced activity of alkaline phosphatase and osteocalcin in hOB (with no synergism with IL-1). MSUM- or CPPD-stimulated expression of IL-6 in hOB pretreated with the selective cyclooxygenase-2 inhibitor NS-398 was increased, unlike that induced by IL-1 alone which was partially reduced. MSUM-, CPPD- or IL-1-induced expression of IL-8 was unchanged by pretreating hOB with NS-398. These results suggest that inflammatory microcrystals alter the normal phenotype of hOB, redirecting them toward reduced bone formation and amplified osteoblast-mediated bone resorption, abnormalities that could play a role in the bone destruction associated with chronic crystal-induced arthritis.
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PMID:Inflammatory microcrystals alter the functional phenotype of human osteoblast-like cells in vitro: synergism with IL-1 to overexpress cyclooxygenase-2. 1199 89

Whether non-steroidal anti-inflammatory drug (NSAID)-induced suppression of bone ingrowth is due to cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, or through a yet unidentified pathway is unknown. In this study, the effects of a non-specific COX-1 and COX-2 inhibitor, versus a specific COX-2 inhibitor on bone ingrowth and tissue differentiation are examined in vivo. Harvest chambers were implanted unilaterally in the tibiae of eight mature, New Zealand white rabbits. After a 6-week period for osseointegration of the chamber, the following oral treatments were given for 4 weeks each, followed by a harvest in each case: drinking water with no NSAID (control 1), Naproxen sodium--a COX-1 and COX-2 non-specific inhibitor at a dose of 110 mg/kg/day in the drinking water, drinking water with no NSAID (control 2), and Rofecoxib-a COX-2 inhibitor at a dose of 12.5 mg/day inserted directly into the rabbit's mouth. Harvested specimens were snap frozen, cut into serial 6 microm sections and stained with hematoxylin and eosin for general morphological characterization, and alkaline phosphatase (osteoblast marker). Sections were also processed for immunoperoxidase staining using monoclonal antibodies to identify cells expressing the vitronectin receptor (osteoclast-like cells). With drinking water alone, the percentage of bone ingrowth averaged 24.8 +/- 2.9% and 29.9 +/- 4.5% respectively. Naproxen sodium in the drinking water and oral Rofecoxib decreased bone ingrowth significantly (15.9 +/- 3.3%. p = 0.031 and 18.5 +/- 2+/-4%, p = 0.035 compared to drinking water respectively). Both Naproxen sodium (p = 0.026) and Rofecoxib (p = 0.02) decreased the number of CD51 positive osteoclast-like cells per section compared with drinking water alone. Rofecoxib decreased the area of osteoblasts per section area (p = 0.014) compared to controls, although the value for Naproxen sodium did not reach statistical significance. The results of the present study suggest that bone formation is suppressed by oral administration of an NSAID which contains a COX-2 inhibitor. COX-2 inhibitors currently taken for arthritis and other conditions may potentially delay fracture healing and bone ingrowth.
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PMID:COX-2 selective NSAID decreases bone ingrowth in vivo. 1247 24

Prostaglandins are ubiquitous metabolites of arachidonic acid, and cyclooxygenase inhibitors prevent their production and secretion. Animals with loss of cyclooxygenase-2 function have reduced reparative bone formation, but the role of prostaglandins during endochondral bone formation is not defined. The role of PGE2 as a regulator of chondrocyte differentiation in chick growth plate chondrocytes (GPCs) was examined. While PGE2, PGD2, PGF2alpha, and PGJ2 all inhibited colX expression, approximately 80% at 10(-6) M, PGE2 was the most potent activator of cAMP response element (CRE)-mediated transcription. PGE2 dose-dependently inhibited the expression of the differentiation-related genes, colX, VEGF, MMP-13, and alkaline phosphatase gene, and enzyme activity with significant effects at concentrations as low as 10(-10) M. PGE2 induced cyclic AMP response element binding protein (CREB) phosphorylation and increased c-Fos protein levels by 5 min, and activated transcription at CRE-Luc, AP-1-Luc, and c-Fos promoter constructs. The protein kinase A (PKA) inhibitor, H-89, completely blocked PGE2-mediated induction of CRE-Luc and c-Fos promoter-Luc promoters, and partially inhibited induction of AP-1-Luc, while the protein kinase C (PKC) inhibitor Go-6976 partially inhibited all three promoters, demonstrating substantial cross-talk between these signaling pathways. PGE2 inhibition of colX gene expression was dependent upon both PKA and PKC signaling. These observations demonstrate potent prostaglandin regulatory effects on chondrocyte maturation and show a role for both PKA and PKC signaling in PGE2 regulatory events.
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PMID:PGE2 inhibits chondrocyte differentiation through PKA and PKC signaling. 1538 23

Drynariae Rhizoma (DR), a traditional Korea medicine, which is known for its effect to strengthen myoskeletal systems, frequently appears as the main ingredient in prescriptions for bone injuries. However, it is unclear how it pharmacologically contributes to the reformation of bone. In this study, the effect of DR on bone cells was investigated in vitro for the first time. The human osteoprecursor cells (OPC-1) were incubated in the medium with different concentrations of DR and the cell proliferation was studied. When the concentration of DR was < or = 120 microg ml(-1), the proliferation of OPC-1 was enhanced. However, the proliferation of OPC-1 was inhibited by DR with the concentrations of > 250 microg ml(-1). Under most treatments, the cells presented very pale expression for cyclooxygenase-2 (Cox-2) protein; slightly intensified band showed at the highest DR concentration, 120 microg ml(-1) during the course of culture. On the other hand, we investigated the immunomodulatory activity of DR on cellular and humoral immunity. When different doses of ethanolic and water extracts of DR was administered to mice, it was dose-dependently potentiated the delayed-type hypersensitivity reaction induced by both sheep red blood cells (SRBC) and oxazolone. It significantly enhanced the production of circulating antibody titre in mice in response to SRBC. But, DR did not any effect on macrophage phagocytosis. Prolonged administration of DR significantly ameliorated the total white blood cell count and also restored the immunosuppressive effects induced by cyclophosphamide. The present investigation reveals that DR possesses immunomodulatory activity. From the results, it was concluded that DR directly stimulated the proliferation, alkaline phosphatase activity, protein secretion and particularly type I collagen synthesis of OPC-1 at dose-dependent manner, and stimulated both the cellular and the humoral immunity.
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PMID:Effects of Drynariae rhizoma on the proliferation of human bone cells and the immunomodulatory activity. 1562 57

Tissue formation and repair are dependent upon cascades of biological events, but the signals involved and the possible gene coexpression patterns during intramembranous bone repair are only poorly understood. We sought to place this mode of regeneration in context by profiling quantitative gene expression for a panel of 39 genes between days 1 and 14 following rat femoral marrow ablation. In situ hybridization was employed to localize a subset of genes. Additionally, principal components analysis was conducted to identify underlying factors suggestive of coexpression patterns. During inflammation (days 1-5), several genes, including cyclooxygenase-1 and -2, showed downregulation. Other proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta, exhibited increasing levels around day 5. During repair (days 3-10), growth factors, receptors, and inhibitor genes for transforming growth factor- beta; basic fibroblast growth factor; bone morphogenetic proteins 2, 4, and 7; vascular endothelial growth factor; and insulin-like growth factor-I were upregulated. In addition, the gene for core binding factor-alpha1 and markers of osteoblast function such as alkaline phosphatase, collagen type I, osteonectin, osteopontin, and osteocalcin had peak expression at day 5 or 7. The remodeling phase (days 10-14) was characterized by peaks for cytokines associated with osteoclastic activity including receptor activator of nuclear factor-kappaB, receptor activator of nuclear factor-kappaB ligand (RANKL), cathepsin K, tumor necrosis factor-alpha, interleukin-6, and cyclooxygenase-2. In situ hybridization showed that the most common sites of increased signal were within osteoblastic cells on trabecular and endosteal surfaces. Principal components analysis identified eight underlying factors that together explained over 80% of the variance in the data.
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PMID:Patterns and localization of gene expression during intramembranous bone regeneration in the rat femoral marrow ablation model. 1619 34

The present study was designed to evaluate the effect of two commonly prescribed non-steroidal anti-inflammatory drugs (NSAIDs) with varying cyclooxygenase-2 (Cox-2) selectivities on enzyme activities and transport properties of rat intestinal brush border membrane (BBM). Female Wistar rats were divided into three different groups, viz: Group I (Control), Group II (aspirin-treated, 50 mg/kg) and Group III (nimesulide-treated, 10 mg/kg). At the end of 28 days of treatment, membranes were isolated from different intestinal segments of all the groups and changes in BBM-associated enzymes such as sucrase, lactase, maltase, alkaline phosphatase and the transport properties of D-glucose and its kinetics were studied. The results indicated a significant decrease in the activities of enzymes and transport of glucose in both the treatment groups as compared to the controls. Changes in Michaelis-Menten parameters, viz:--Km and Vmax and the thermodynamic parameters T(c) and E(a) were also seen which are indicative of adverse effects of these two NSAIDs in the intestinal membrane such as the membrane integrity.
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PMID:Effect of two non-steroidal anti-inflammatory drugs, aspirin and nimesulide on the D-glucose transport and disaccharide hydrolases in the intestinal brush border membrane. 1638 4


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