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)

Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) have been implicated in the pathogenesis of osteoporosis. These proinflammatory cytokines induce both cyclooxygenase (COX) and nitric oxide synthase (NOS) with the release of prostaglandin (PG) and NO, respectively. The present study was undertaken to examine the interaction between COX and NOS pathways and their role in the regulation of osteoblastic function in MC3T3-E1 cells. Addition of IL-1 alpha and TNF-alpha induced a marked increase in the production of both NO and PGE2. Reverse transcription-polymerase chain reaction analysis showed that the increase in NO production was preceded by the expression of inducible NOS mRNA. The temporal profile of PGE2 production revealed a biphasic pattern: the first small peak at 3 h was caused by de novo synthesis of PGE2 through inducible COX (COX-2) mRNA, while the subsequent progressive accumulation of PGE2 was mediated through the activation of COX pathway by NO since (1) aminoguanidine (AG), a selective inhibitor of inducible NOS, significantly suppressed the PGE2 production by IL-1 alpha and TNF-alpha, (2) NOC-18, an NO donor, reversed this suppression, and (3) NOC-18 increased PGE2 production by itself. The increase in NO production in response to IL-1 alpha and TNF-alpha was further stimulated by aspirin and inhibited by exogenous addition of PGE2, suggesting that PGE2 produced by the cytokines, in turn, negatively modulates NO production. IL-1 alpha and TNF-alpha inhibited alkaline phosphatase (ALP) activity, which was significantly reversed by AG. NOC-18 not only suppressed ALP activity by itself but also blocked the effect of AG, suggesting the role of NO in the inhibition of ALP activity. PGE2 decreased ALP activity, and the inhibitory effect of NOC-18 was attenuated in the presence of aspirin, suggesting the involvement of PGE2 in the negative modulation of ALP activity by NO. These results suggest that NO produced in response to proinflammatory cytokines participates in the modulation of ALP activity via the activation of COX pathway. The interaction between NO and the COX pathways may play an important role in the regulation of osteoblastic functions under physiologic as well as pathologic conditions.
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PMID:Interaction between nitric oxide synthase and cyclooxygenase pathways in osteoblastic MC3T3-E1 cells. 938 83

1,25-(OH)2D3 (1,25) exerts its effects on growth plate chondrocytes through classical vitamin D (VDR) receptor-dependent mechanisms, resulting in mineralization of the extracellular matrix. Recent studies have shown that membrane-mediated mechanisms are involved as well. 1,25 targets cells in the prehypertrophic and upper hypertrophic zones of the costochondral cartilage growth plate (GC cells), resulting in increased specific activity of alkaline phosphatase (ALP), phospholipase A2 (PLA2), and matrix metalloproteinases (MMPs). At the cellular level, 1,25 action results in rapid changes in arachidonic acid (AA) release and re-incorporation, alterations in membrane fluidity and Ca ion flux, and increased prostaglandin E1 and E2 (PGE2) production. Protein kinase C (PKC) is activated in a phospholipase C (PLC) dependent-mechanism, due in part to the increased production of diacylglycerol (DAG). In addition, AA acts directly on the cell to increase PKC specific activity. AA also provides a substrate for cyclooxygenase (COX), resulting in PGE2 production. 1,25 mediates its effects through COX-1, the constitutive enzyme, but not COX-2, the inducible enzyme. Time course studies using specific inhibitors of COX-1 show that AA stimulates PKC activity and PKC then stimulates PGE2 production. PGE2 acts as a mediator of 1,25 action on the cells, also stimulating PKC activity. The rapid effects of 1,25 on PKC are nongenomic, occurring within 3 min and reaching maximal activation by 9 min. It promotes translocation of PKC to the plasma membrane. When 1,25 is incubated directly with isolated plasma membranes, PKCalpha is stimulated although PKCzeta is also present. In contrast, when isolated matrix vesicles (MVs) are incubated with 1,25, PKCzeta is inhibited and PKCalpha is unaffected. These membrane-mediated effects are due to the presence of a specific membrane vitamin D receptor (mVDR) that is distinct from the classical cytosolic VDR. Studies using 1,25 analogs with reduced binding affinity for the classical VDR, confirm that rapid activation of PKC by 1,25 is not VDR dependent. The membrane-mediated effects of 1,25 are critical to the regulation of events in the extracellular matrix produced by the chondrocytes. MVs are extracellular organelles associated with maturation of the matrix, preparing it for mineralization. MV composition is under genomic control, involving VDR-mechanisms. In the matrix, no new gene expression or protein synthesis can occur, however. Differential distribution of PKC isoforms and their nongenomic regulation by 1,25 is one way for the chondrocyte to control events at sites distant from the cell. GC cells contain 1a-hydroxylase and produce 1,25; this production is regulated by 1,25, 24,25, and dexamethasone. 1,25 stimulates MMPs in the MVs, resulting in increased proteoglycan degradation in mineralization gels, and increased activation of latent transforming growth factor-beta 1 (TGF-beta1).
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PMID:1,25-(OH)2D3 modulates growth plate chondrocytes via membrane receptor-mediated protein kinase C by a mechanism that involves changes in phospholipid metabolism and the action of arachidonic acid and PGE2. 1032 81

In a search for new inhibitors of the IFN-gamma mediated signal transduction in HeLa S3 cells using secreted alkaline phosphatase (SEAP) as reporter gene, the novel pyran-dione trichodion was isolated from fermentations of the imperfect fungus Trichosporiella sp. 20-95. The compound inhibits the IFN-gamma mediated expression of the reporter gene with IC(50) values of 21-42 microM (5-10 microgram/ml). The NF-kappaB and AP-1 mediated expression of the reporter gene are inhibited with IC(50) values of 42-84 microM (10-20 microgram/ml) and 21 microM (5 microgram/ml) respectively. Western blotting with COX-2 and NOS II antibodies showed that the expression of both proinflammatory enzymes is almost completely inhibited at 21-42 microM (5-10 microgram/ml) in LPS/IFN-gamma stimulated J774 mouse macrophages. Studies on the mode of action of the compound revealed that the inhibition of the NF-kappaB dependent pathway is due to the stabilization of the IkappaB protein and the inhibition of the IFN-gamma dependent signaling is caused by an inhibition of the phosphorylation of the STAT1alpha transcription factor.
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PMID:Trichodion, a new inhibitor of inflammatory signal transduction pathways from a Trichosporiella species. 1090 24

Recent investigations indicate that the type and amount of polyunsaturated fatty acids (PUFA) influence bone formation in animal models and osteoblastic cell functions in culture. In growing rats, supplementing the diet with omega-3 PUFA results in greater bone formation rates and moderates ex vivo prostaglandin E(2) production in bone organ cultures. A protective effect of omega-3 PUFA on minimizing bone mineral loss in ovariectomized rats has also been reported. The actions of omega-3 fatty acids on bone formation appear to be linked to altering osteoblast functions. Herein we describe experiments with MC3T3-E1 osteoblast-like cells that support findings in vivo where omega-3 PUFA modulated COX-2 protein expression, reduced prostaglandin E(2) production, and increased alkaline phosphatase activity. Other studies indicate that the dietary source of PUFA may affect protein expression of Cbfa1 and nodule formation in fetal rat calvarial cells.
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PMID:Modulatory effect of omega-3 polyunsaturated fatty acids on osteoblast function and bone metabolism. 1279 59

In a search for new inhibitors of the IFN-gamma mediated signal transduction in HeLa S3 cells using secreted alkaline phosphatase (SEAP) as reporter gene, a novel compound, designated as S14-95 was isolated from fermentations of the imperfect fungus Penicillium sp. 14-95. The compound inhibits the IFN-gamma mediated expression of the reporter gene with IC50 values of 2.5 to approximately 5 microg/ml (5.4 to approximately 10.8 microM). Furthermore the compound inhibited the expression of the proinflammatory enzymes COX-2 and NOS II at 5 microg/ml (10.8 microM) in LPS/IFN-gamma stimulated J774 mouse macrophages. Studies on the mode of action of the compound revealed that the inhibition of the IFN-gamma dependent signaling pathway is caused by an inhibition of the phosphorylation of the STAT1alpha transcription factor. In addition, S14-95 inhibited the activation of the p38 MAP kinase, which is involved in the inducible expression of many proinflammatory genes.
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PMID:S14-95, a novel inhibitor of the JAK/STAT pathway from a Penicillium species. 1281 6

There is increasing evidence that non-steroidal anti-inflammatory drugs (NSAIDs) can adversely affect bone repair. We have, therefore, studied the in vitro effects of NSAIDs, which differentially inhibit cyclooxygenases (COX), the prostaglandin/thromboxane synthesising enzymes, on human osteoblasts. Indomethacin and the new nitric oxide (NO)-donating NSAIDs block the activity of both COX-1 and COX-2. Indomethacin and 5,5-dimethyl-3-(3 fluorophenyl)-4-(4 methylsulphonal) phenyl-2 (5H)-furanone (DFU) reduced osteoblast numbers in a dose-dependant manner and increased collagen synthesis and alkaline phosphatase activity. The reduction in osteoblast numbers was not caused by loss of adhesion and was reversible. Neither NSAID influenced DNA synthesis. There was no difference between the effects of indomethacin and DFU. NO-NSAIDs did not affect cell numbers. These results suggest that care should be taken when administering NSAIDs to patients with existing skeletal problems and that NO-NSAIDs may be safer.
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PMID:The influence on human osteoblasts in vitro of non-steroidal anti-inflammatory drugs which act on different cyclooxygenase enzymes. 1512 36

Cyclooxygenase (COX)-2, the recently described inducible form ofcyclooxygenase, has been shown to be responsible for the inflammatory and tumorigenic effects of prostaglandins; hence the development and expanding clinical use of COX-2 selective inhibitors termed super aspirins. These pharmacologic agents block COX-2 without abrogating the desired physiologic roles of the constitutively expressed isoform COX-1. Therefore, they are now used in place of nonselective COX inhibitors in patients who require prolonged use of nonsteroidal anti-inflammatory agents. However, there are sporadic reports of COX-2-related nephrotoxicity, and the mechanism of this adverse reaction is not known. Also, the pattern of in situ expression of COX-2 in the human kidney is not known. We therefore studied the immunohistochemical expression of COX-2 in normal kidneys obtained from 53 consecutive total nephrectomy specimens. COX-2 immunohistochemistry was performed using affinity purified polyclonal murine antibody and avidin-biotin detection method with citrate antigen retrieval. Also, to localize COX-2 expression to specific cell types, double immunolabeling was performed using avidin-biotin (for COX-2 detection) and alkaline phosphatase (for detection of alpha-smooth muscle actin or factor VIII related antigen). In the cortex, COX-2 was found to be constitutively expressed in the endothelial cells of arteries, arterioles, and glomeruli in all 53 kidneys. COX-2 expression was also found in the cortical thick ascending limb of the loop of Henle (medullary rays and macula densa) in 50 of 53 cases. In the medulla, COX-2 expression was detected in the endothelial lining of the vasa recta in 52 cases and in the collecting ducts in 5 cases. These data show significant constitutive expression of COX-2 in normal kidney and underscore the need for caution in the use of COX-2 selective inhibitors, especially on a long-term basis.
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PMID:Immunohistochemical expression of cyclooxygenase-2 in normal kidneys. 1516 23

The effects of a short course of a COX-2 inhibitor on bone healing when the drug is discontinued are unknown. We examined the effects of rofecoxib on bone ingrowth over a 6-week period using a well-defined animal model. The Bone Harvest Chamber was implanted bilaterally in mature rabbits. After osseointegration of the chamber, the following treatments were given for 6 weeks each, followed by a harvest in each case: control-no drug; oral rofecoxib (12.5 mg/day) for the first 2 of 6 weeks; washout period-no drug; oral rofecoxib for the last 2 of 6 weeks; washout period-no drug; rofecoxib given continuously for all 6 weeks. Harvested specimens were snap-frozen, cut into serial 6-microm sections, and stained with hematoxylin and eosin and alkaline phosphatase (osteoblast marker), and processed using immunohistochemistry to identify the vitronectin receptor (osteoclast-like cells). Rofecoxib given continuously for 6 weeks yielded statistically less bone ingrowth compared to the control treatment. Rofecoxib given during the initial or final 2 weeks of a 6-week treatment did not appear to interfere with bone ingrowth. This suggests that the effects of COX-2 inhibitors on bone are less profound when the drug is administered for a short period of time.
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PMID:Temporal effects of a COX-2-selective NSAID on bone ingrowth. 1566 61

Previous studies have indicated that one of the causes of alveolar bone destruction with periodontitis is lipopolysaccharide (LPS) from the cell wall of gram-negative bacteria in plaque, and that prostaglandin E(2) (PGE(2)) is one of the bone resorption factors that stimulate osteoclast formation through an intercellular interaction between osteoblasts and osteoclast precursors. The present study was undertaken to determine the effect of LPS on cell growth, alkaline phosphatase (ALPase) activity, the production of PGE(2), and the expression of receptors by PGE(2), cyclooxygenase (COX)-1, and COX-2, using human osteosarcoma cell line Saos-2 as osteoblasts. The cells were cultured with 0, 1, or 10 microg mL(-1) of LPS for up to 14 days. The production of PGE(2) and the gene expression of COX-1, COX-2, and PGE(2) receptors, including Ep1, Ep2, Ep3, and Ep4, were determined using enzyme-linked immunosorbent assay (ELISA) and real-time reverse transcription-polymerase chain reaction (real-time RT-PCR), respectively. With the addition of LPS, cell growth and ALPase activity decreased by day 5 of the culture, while PGE(2) production increased in a dose-dependent manner throughout the entire 14-day culture period. LPS-reduced ALP activity and LPS-induced PGE(2) production returned to the control level by the addition simultaneously with indomethacin. The expression of COX-1, Ep1, Ep2, and Ep3 receptors decreased on day 14 of the culture, whereas the expression of COX-2 and Ep4 receptors increased significantly with the addition of LPS. These results suggest that LPS promotes PGE(2) production by increasing the expression of COX-2, and that LPS promotes the production of Ep4 receptors in osteoblasts. These results also indicate that LPS-induced PGE(2) may combine with osteoblast Ep4 receptors in autocrine or paracrine modes, and may promote the formation of osteoclasts.
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PMID:Lipopolysaccharide stimulates the production of prostaglandin E2 and the receptor Ep4 in osteoblasts. 1628 20

The overexpression of COX enzymes has been demonstrated in human neoplasms at various sites, including the colon, gastrointestinal tract, lung, skin and recently in brain tumors. In this study, COX-2 receptor overexpression in primary childhood brain tumors was determined and the distribution pattern of COX-2 receptors was examined. A sensitive, 4-step, alkaline phosphatase conjugated antigen detection technique was used and a specific monoclonal antibody for medulloblastomas/ primitive neuroectodermal tumors (MEDs/PNETs), anaplastic, high-grade astrocytomas (ASTRs) and in glioblastoma multiformes (GMs) was employed. All of the 14 MEDs/PNETs observed demonstrated high levels of immunoreactivity (overexpression), with the highest immunostaining intensity (grades A and B). However, of the 14 subtypes of astrocytic tumors examined, the COX-2 receptor expression level did not even approach those of the MEDs/PNETs levels. However, significant differences were found when comparing low grade pilocytic ASTRs to high grade anaplastic ASTRs and glioblastomas. In two low grade pilocytic ASTRs, the expression level never exceeded 20%, while in high grade glial tumors (6 anaplastic ASTRs and 6 GMs) 30 to 50% of the tumor cells overexpressed COX-2 receptors, documenting an increase in COX-2 receptor overexpression with the increasing grade of the astrocytic tumor. In view of these findings, it would appear likely that COX-2 inhibitors may represent a chemo-preventive tool in treating childhood brain tumors, which are the leading cause of solid tumor cancer death in children under the age of 20.
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PMID:Cyclooxygenase-2 (COX-2) overexpression in childhood brain tumors. 1690 Jul 83


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