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 commencement of the complex process of carcinogenesis, and subsequent, rapid tumor growth and progression of mammalian neoplasms, including malignant melanomas, depends upon the continuous de novo formation of capillaries [i.e. neovascularization (NV)/neoplasm-related angiogenesis (NRA)]. The generation of a dedifferentiated, malignant, highly invasive cellular immunophenotype (CIP) and distant metastases, as aspects of constant neoplastic progression, are also NRA-dependent processes. Endothelial cells undergo rapid proliferation during malignant melanoma (MM) related angiogenesis. Human endoglin (CD105/EDG), is a homodimeric cell surface component of the transforming growth factor-beta (TGF-beta) type I receptor complex and is also a proliferation-associated antigen (PAA) expressed at high density on endothelial cells. Formalin fixed, paraffin-wax embedded, tissue sections (3-5 microns thick) of 25 MMs were employed for the assessment of EDG expression. An indirect, four-step, alkaline phosphatase (AP) (or diamino-benzidine [DAB]) conjugated, biotin-streptavidin based, antigen detection technique, employing the SN6h anti-EDG monoclonal antibody was conducted. Zymed's Histogold System was also utilized for immunocytological antigen detection. Strong expression (A; +3 to +4) of EDG on endothelial cells was demonstrated in all MM cases. The most striking feature of the newly formed neoplasm-related capillaries was the presence of an enlarged perivascular space. Blood vessels in several normal human tissues (cortex, cerebellum, thymus, tonsil, spleen, lymph node, skin) used as control tissues contained significantly lower levels of EDG (B and mostly C; +/- to +), in accordance with the extremely slow turnover rate of normal endothelial cells. Furthermore, a close apposition between the capillaries and the adjacent parenchyma was observed in these normal controls. MMs, like most mammalian neoplasms, are characterized by extensive neovascularization, and thus are candidates for anti-angiogenic therapy. Further studies should substantiate the importance of EDG expression in the earliest possible detection, diagnosis and NRA inhibition-based treatment of solid tumors, including MMs. The importance of TGF-beta in all of the various aspects of neoplastic transformation, as well as malignant disease progression should also be studied more extensively in the future.
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PMID:Immunocytochemical detection of endoglin is indicative of angiogenesis in malignant melanoma. 970 32

The commencement of the complex process of carcinogenesis, and subsequent, rapid tumor growth and progression of mammalian neoplasms, including breast carcinomas (BCs), depends upon the continuous de novo formation of capillaries [i.e. neovascularization (NV)/neoplasm-related angiogenesis (NRA)]. The generation of a malignant, invasive cellular immunophenotype (CIP) and distant metastases, as aspects of tumor progression, are also NRA-dependent processes. Endothelial cells undergo rapid proliferation during mammary carcinoma-related angiogenesis. Human endoglin (CD105/EDG), is a homodimeric cell surface component of the transforming growth factor-beta (TGF-beta) type I receptor complex and is also a proliferation-associated antigen (PM) expressed at high density on endothelial cells. Formalin fixed, paraffin-wax embedded, tissue sections (3-5 microns thick) of 15 BCs were employed for the assessment of EDG expression. An indirect, four-step, alkaline phosphatase (AP) (or diamino-benzidine [DAB]) conjugated, biotin-streptavidin based, antigen detection technique, employing the SN6h anti-EDG monoclonal antibody was conducted. Zymed's Histogold System was also utilized for immunocytological antigen detection. Strong expression (A; ++ + to ++ ++) of EDG on endothelial cells was demonstrated in all 15 BC cases. The most striking feature of the newly formed neoplasm-related capillaries was the presence of an enlarged perivascular space. Blood vessels in several normal human tissues (cortex, cerebellum, thymus, tonsil, spleen, lymph node, skin) used as control tissues contained significantly lower levels of EDG (B and mostly C; +/- to +), in accordance with the extremely slow turnover rate of normal endothelial cells. Furthermore, a close apposition between the capillaries and the adjacent parenchyma was observed in these normal controls. BCs, as most mammalian neoplasms, are characterized by extensive neovascularization and thus are candidates for anti-angiogenic therapy. Further studies should substantiate the importance of EDG expression in the earliest possible detection, diagnosis and NRA inhibition-based treatment of solid tumors, including BCs.
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PMID:Over-expression of endoglin (CD105): a marker of breast carcinoma-induced neo-vascularization. 985 49

The success of an implant is determined by its integration into the tissue surrounding the biomaterial. Surface roughness and composition are considered to influence the properties of adherent cells. The aim of this study was to determine the effect of chemical composition and surface roughness of commercially pure titanium (Ti) and Ti-6A1-4V alloy (Ti-A) on MG63 osteoblast-like cells. Unalloyed and alloyed Ti disks were machined and either fine-polished or wet-ground, resulting in smooth (S) and rough (R) finishes, respectively. Standard tissue culture plastic was used as a control. Surface topography and profile were evaluated by cold field emission scanning electron microscopy and profilometry, while chemical composition was determined using Auger electron spectroscopy and Fourier transform infrared spectroscopy. The effect on the cells was evaluated 24 h postconfluence by measuring cell number, [3H]-thymidine incorporation into DNA, cell and cell layer alkaline phosphatase specific activity (ALPase), osteocalcin and collagen production, [35S]-sulfate incorporation into proteoglycan, and prostaglandin E2 (PGE2) and transforming growth factor-beta (TGF-beta) production. When compared to plastic, the number of cells was reduced on the pure Ti surfaces, while it was equivalent on the Ti-A surfaces; [3H]-thymidine incorporation was reduced on all surfaces. The stimulatory effect of surface roughness on ALPase in isolated cells and the cell layer was more pronounced on the rougher surfaces, with enzyme activity on Ti-R being greater than on Ti-A-R. Osteocalcin production was increased only on the Ti-R surface. Collagen production was decreased on Ti surfaces except Ti-R; [35S]-sulfate incorporation was reduced on all surfaces. Surface roughness affected local factor production (TGF-beta, PGE2). The stimulatory effect of the rougher surfaces on PGE2 and TGF-beta was greater on Ti than Ti-A. In summary, cell proliferation, differentiation, protein synthesis and local factor production were affected by surface roughness and composition. Enhanced differentiation of cells grown on rough vs. smooth surfaces for both Ti and Ti-A surfaces was indicated by decreased proliferation and increased ALPase and osteocalcin production. Local factor production was also enhanced on rough surfaces, supporting the contention that these cells are more differentiated. Surface composition also played a role in cell differentiation, since cells cultured on Ti-R surfaces produced more ALPase than those cultured on Ti-A-R. While it is still unknown which material properties induce which cellular responses, this study suggests that surface roughness and composition may play a major role and that the best design for an orthopaedic implant is a pure titanium surface with a rough microtopography.
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PMID:Response of MG63 osteoblast-like cells to titanium and titanium alloy is dependent on surface roughness and composition. 988 63

Retinoic acid-induced differentiation of the pre-osteoblastic cell line, UMR 201, is associated with a marked increase in the proficiency of posttranscriptional nuclear processing of alkaline phosphatase mRNA. In this study we attempted to correlate the posttranscriptional actions of retinoic acid with changes in phosphorylation, or abundance of spliceosome components, or both. Treatment with retinoic acid for periods of < or = 4 h resulted in dephosphorylation of nuclear U1 70K protein without affecting its abundance. Peptide mapping showed that U1 70K dephosphorylation was related to the disappearance of one specific phosphopeptide out of four major U1 70K phosphopeptides. A twofold decrease in mRNA expression of an isoform of alternative splicing factor that inhibits splicing was also observed over the same period. Tumor necrosis factor-alpha, which enhances the posttranscriptional action of retinoic acid, reduced U1 70K mRNA expression, while an inhibition of retinoic acid action by transforming growth factor-beta was associated with a marked increase in U1 70K mRNA levels. Our results draw attention to the complex interactions between short- and long-term alterations in the abundance and functional status of U1 70K, as well as SR proteins by growth and/or differentiation factors in the regulation of spliceosome formation and function.
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PMID:Dual posttranscriptional targets of retinoic acid-induced gene expression. 1002 22

Small particles of ultrahigh molecular weight polyethylene stimulate formation of foreign-body granulomas and bone resorption. Bone formation may also be affected by wear debris. To determine if wear debris directly affects osteoblasts, we characterized a commercial preparation of ultrahigh molecular weight polyethylene (GUR4150) particles and examined their effect on MG63 osteoblast-like cells. In aliquots of the culture medium containing ultrahigh molecular weight polyethylene, 79% of the particles were less than 1 microm in diameter, indicating that the cells were exposed to particles of less than 1 microm. MG63 cell response to the particles was measured by assaying cell number, [3H]thymidine incorporation, alkaline phosphatase specific activity, osteocalcin production, [35S]sulfate incorporation, and production of prostaglandin E2 and transforming growth factor-beta. Cell number and [3H]thymidine incorporation were increased in a dose-dependent manner. Alkaline phosphatase specific activity, a marker of cell differentiation for the cultures, was significantly decreased, but osteocalcin production was not affected. [35S]sulfate incorporation, a measure of extracellular matrix production, was reduced. Prostaglandin E2 release was increased, but transforming growth factor-beta production was decreased in a dose-dependent manner. This shows that ultrahigh molecular weight polyethylene particles affect MG63 proliferation, differentiation, extracellular matrix synthesis, and local factor production. These effects were direct and dose dependent. The findings suggest that ultrahigh molecular weight polyethylene wear debris particles with an average size of approximately 1 microm may inhibit bone formation by inhibiting cell differentiation and reducing transforming growth factor-beta production and matrix synthesis. In addition, increases in prostaglandin E2 production may not only affect osteoblasts by an autocrine pathway but may also stimulate the proliferation and activation of cells in the monocytic lineage. These changes favor decreased bone formation and increased bone resorption as occur in osteolysis.
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PMID:Ultrahigh molecular weight polyethylene particles have direct effects on proliferation, differentiation, and local factor production of MG63 osteoblast-like cells. 1007 42

In this study, the specific objective was to investigate the combined effect of different treatments of transforming growth factor-beta (TGF-beta) and hydroxyapatite (HA) on osteoblast response in vitro. Since the nature of bone cell responses in vitro is influenced by the properties of HA ceramics, this study was divided into 2 components: a chemical and crystallographic characterization of the HA ceramics, and an in vitro cell culture study. Sintered HA samples were observed to have the highest crystallite size, compared to as-received HA and calcined HA samples. No differences in surface roughness and chemical composition were observed between the sintered, calcined, and as-received HA surfaces. In concurrence with the x-ray diffraction, high-resolution x-ray photoelectron spectroscopy of Ca 2p also indicated a higher crystallinity on sintered HA samples compared to calcined and as-received HA samples. Protein production by osteoblast cells was not statistically different on the 3 HA surfaces in the absence of TGF-beta. However, there was a dose-dependent increase in TGF-beta-stimulated protein production on the 3 different HA surfaces. As indicated by increased alkaline phosphatase-specific activity, as well as 1,25 (OH2) vitamin D3-stimulated osteocalcin production, a more differentiated osteoblastlike phenotype was observed on the sintered HA surfaces compared to the as-received HA and calcined HA surfaces. An increased osteoblast-like cell activity on sintered HA surfaces in the presence of different TGF-beta dosage suggested that sintering of HA surfaces may play an important role in governing cellular response.
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PMID:Effect of transforming growth factor-beta on osteoblast cells cultured on 3 different hydroxyapatite surfaces. 1021 38

During endochondral bone formation, as occurs in fracture healing, chondrocytes are one of the first cells to see an implant surface. We tested the hypothesis that chemical composition and surface roughness affect chondrocyte differentiation, matrix synthesis, and local factor production and that the nature of the response is dependent on the state of maturation of the cells. To do this, we harvested rat growth zone and resting zone chondrocytes and examined their response to smooth and rough disk surfaces manufactured from either commercially pure titanium or titanium alloy. Profilometry, scanning electron microscopy, Auger spectroscopy, and Fourier transform infrared spectroscopy were used to characterize the surfaces. Average roughness values were 0.22 microm for smooth titanium surfaces, 0.23 microm for smooth titanium alloy surfaces, 4.24 microm for rough titanium surfaces, and 3.20 microm for rough titanium alloy surfaces. Cells were grown on the different disk surfaces until the cultures had reached confluence on plastic. The effect of the surfaces was determined by assaying cell number and [3H]thymidine incorporation as measures of cell proliferation, cell layer and cell alkaline phosphatase specific activity as markers of differentiation, and collagen production and [35S]sulfate incorporation as indicators of extracellular matrix production. In addition, the synthesis of prostaglandin E2 and transforming growth factor-beta were examined to measure changes in local factor synthesis. In growth zone and resting zone cultures, cell number and [3H]thymidine incorporation were decreased on rough surfaces; however, this effect was greater on commercially pure titanium surfaces. Cell layer and cell alkaline phosphatase specific activity were decreased in resting zone cells grown on rough surfaces. Cell alkaline phosphatase specific activity in growth zone cells was decreased on rough surfaces, whereas cell layer alkaline phosphatase specific activity was increased only in growth zone cells grown on rough commercially pure titanium surfaces. Resting zone cell collagen production was decreased only on rough commercially pure titanium, whereas in growth zone cells, collagen production was increased. Increased prostaglandin E2 release into the media was found for growth zone and resting zone cell cultures on the disks with rough surfaces. The observed effect was greater on rough commercially pure titanium. Production of transforming growth factor-beta by resting zones was similarly affected, whereas an increase in its production by growth zone cells was measured only on rough commercially pure titanium. These results indicate that surface roughness affects chondrocyte proliferation, differentiation, matrix synthesis, and local factor production and that these parameters are also affected by chemical composition. Furthermore, the nature and extent of the cell response is dependent on cell maturation. The overriding variable in response to an implant material, however, appears to be roughness of the surface.
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PMID:Effect of surface roughness and composition on costochondral chondrocytes is dependent on cell maturation state. 1037 36

Heparan-like polymers derived from dextran, named RGTA, were shown to stimulate bone repair in different bone defect models. Like heparin and heparan sulfates, RGTA potentiate in vitro the biological activities of heparin-binding growth factors (HBGFs), such as fibroblast growth factor (FGF), by stabilizing them against denaturations and by enhancing their binding with cellular receptors. RGTA were postulated to stimulate bone healing by interacting with HBGFs released in the wound site and, subsequently, by promoting the proliferation and/or differentiation of cells implicated in this process. We examined the effects of RGTA alone and associated with HBGFs on MC3T3-E1 osteoblastic cell proliferation and differentiation. RGTA inhibited cell proliferation, as measured by [3H]-thymidine incorporation into DNA. They enhanced the inhibition of DNA synthesis caused by transforming growth factor-beta (TGF-beta1) and bone morphogenetic protein-2 (BMP-2). RGTA alone increased the alkaline phosphatase and parathyroid hormone-responsive adenylate cyclase activities in MC3T3. RGTA enhanced the stimulation of the alkaline phosphatase activity induced by BMP-2 and decreased or suppressed the inhibition caused by TGF-beta1 and FGF-2. Furthermore, RGTA increased the response to parathyroid hormone stimulated by BMP-2. In conclusion, RGTA stimulate the expression of osteoblast phenotype features alone or in association with HBGFs. The ability to promote the differentiation of bone-forming cells is a potential explanation of the stimulating effect of RGTA on bone repair.
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PMID:Effects of heparan-like polymers associated with growth factors on osteoblast proliferation and phenotype expression. 1039 5

Bone morphogenetic protein-2 (BMP-2) is a member of the transforming growth factor-beta (TGF-beta) superfamily and has strong bone-inductive activity in vivo. To examine the role of BMP-2 in an extraskeletal site of rat using a controlled release system of peptides, we encapsulated the recombinant human BMP-2 (rhBMP-2) with poly(DL-lactide-co-glycolide) (PLGA) and implanted the rhBMP-2/PLGA capsules in the subcutaneous area of rats. Upon histochemical examination, it was found that bone-inducing cells having alkaline phosphatase (ALP) activity appeared around the capsules by the suitably released rhBMP-2. In addition, the temporal histological examination showed that direct bone formation without cartilage occurred in the process of this ectopic bone induction. These data indicate that the role of rhBMP-2 in the extraskeletal site of rats is to induce the differentiation of mesenchymal cells into the osteoblasts.
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PMID:The role of recombinant human bone morphogenetic protein-2 in PLGA capsules at an extraskeletal site of the rat. 1039 55

Recent studies of intracellular signal transduction mechanisms for the transforming growth factor-beta (TGF-beta) superfamily have focused on Smad proteins, but have paid little attention to mitogen-activated protein (MAP) kinase cascades. Here we demonstrate that growth/differentiation factor-5 (GDF-5), but neither bone morphogenetic protein-2 (BMP-2) nor TGF-beta1, fully promotes the early phase of the chondrogenic response by inducing cellular condensation followed by cartilage nodule formation in a mouse chondrogenic cell line, ATDC5. We investigated which, if any, of the three major types of MAP kinase plays a functional role in the promotion of chondrogenesis induced by GDF-5. GDF-5 induced phosphorylation of p38 MAP kinase and extracellular signal-regulated kinase (ERK) but not that of c-Jun N-terminal kinase (JNK). The phosphorylation of p38 MAP kinase was also induced by BMP-2 and TGF-beta1. An inhibitor of p38 and p38 beta MAP kinase, SB202190, showed complete inhibition of cartilage nodule formation but failed to affect alkaline phosphatase (ALP) activity induced by GDF-5. Expression of the type II collagen gene, a hallmark of chondrogenesis in vertebrates, was also induced by GDF-5 treatment and strongly suppressed by SB202190. On the other hand, although an inhibitor of MAP/ERK kinase, PD98059, inhibited the rapid phosphorylation of ERK by GDF-5, it inhibited neither ALP activity nor cartilage nodule formation induced by GDF-5. These results strongly suggest that the p38 MAP kinase cascade is involved in GDF-5 signaling pathways and that a role of the p38 MAP kinase pathway is necessary over a longer period to promote chondrogenesis in ATDC5 cells.
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PMID:p38 mitogen-activated protein kinase functionally contributes to chondrogenesis induced by growth/differentiation factor-5 in ATDC5 cells. 1041 89


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