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)

TAK-778 [(2R,4S)-(-)-N-(4-diethoxyphosphorylmethylphenyl)-1,2,4, 5-tetrahydro-4-methyl-7, 8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxyamide; mw 505.53], a novel osteoblast differentiation promoting compound, was characterized in vitro and in vivo models. TAK-778 at doses of 10(-6) M and higher promoted potently bone-like nodule formation in the presence of dexamethasone in rat bone marrow stromal cell culture. This was accompanied by increases in cellular alkaline phosphatase activity, soluble collagen release, and osteocalcin secretion. Under the culture conditions, TAK-778 also stimulated the secretion of transforming growth factor-beta and insulin-like growth factor-I, indicating that TAK-778 may exert regulatory effects on osteoblast differentiation via autocrine/paracrine mechanisms. Furthermore, the in vivo osteogenic potential of TAK-778 was studied in bony defect and osteotomy animal models, using sustained release microcapsules consisted of a biodegradable polymer, poly (dl-lactic/glycolic) acid (PLGA). Single local injection of TAK-778/PLGA-microcapsules (PLGA-MC) (0.2-5 mg/site) to rat skull defects resulted in a dose-dependent increase in new bone area within the defects after 4 weeks. When the pellet containing TAK-778/PLGA-MC (4 mg/pellet) was packed into place to fill the tibial segmental defect in rabbit, this pellet induced osseous union within 2 months, whereas the placebo pellet did not. In addition, single local application of TAK-778/PLGA-MC (10 mg/site) to rabbit tibial osteotomy site enhanced callus formation accompanied by an increase in breaking force after 30 days. These results reveal for the first time that a nonendogenous chemical compound promotes potently osteogenesis in vitro and enhances new bone formation during skeletal regeneration and bone repair in vivo and should be useful for the stimulation of fracture healing.
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PMID:Enhancement of osteogenesis in vitro and in vivo by a novel osteoblast differentiation promoting compound, TAK-778. 1045 78

In addition to playing a central role in thrombosis and hemostasis, the serine protease thrombin is a specific agonist for a variety of functional responses in cells including osteoblast-like cells. Many of the cellular responses to thrombin are mediated by protease-activated receptor-1 (PAR-1). Since osteoblasts express PAR-1 in vivo during development, the effect of PAR-1 activation on proliferation and differentiation in primary rat osteoblast-like cells was investigated. Thrombin or the rat PAR-1-activating peptide SFFLRNPSENTFELVPL (SFFL) stimulated cell proliferation (as assessed by 3H- thymidine incorporation) of primary osteoblast-like cells derived from long bone or calvaria, and treatment with antibodies to PAR-1 abolished the proliferative response to thrombin. Activation of PAR-1 by thrombin or SFFL inhibited endogenous alkaline phosphatase (ALP) activity and caused a transient elevation of intracellular calcium in the osteoblast-like cells. Calcium mobilization was not, however, required for thrombin's effect on proliferation or ALP activity. The ability of a number of growth factors and hormones to regulate expression of PAR-1 in osteoblast-like cells was investigated. Expression of PAR-1 transcript and protein by osteoblast-like cells in vitro was markedly increased by treatment with transforming growth factor-beta (TGF-beta), and the proliferative response to thrombin was enhanced by TGF-beta pretreatment. Platelet-derived growth factor-BB caused a slight but significant down-regulation of PAR-1 mRNA expression. Thrombin caused a transient increase in PAR-1 expression, whereas neither parathyroid hormone-related peptide nor 1, 25-dihydroxyvitamin D3 had any effect. The observations described here suggest that PAR-1 mediates thrombin-induced osteoblast proliferation, which in turn may contribute to responses of osteoblasts to osteogenic growth factors.
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PMID:Modulation of osteoblast-like cell behavior by activation of protease-activated receptor-1. 1045 64

Activin-A is a member of the transforming growth factor-beta (TGF-beta) superfamily and is expressed by osteoblasts. However, the role of activin-A on osteoblasts is not clearly understood. We examined the effects of activin-A on osteoblast proliferation or differentiation, and mineralization by the osteoblasts in the first subcultures of fetal rat osteoblasts obtained from calvarial bones. Exogenous activin-A led to impaired formation of bone nodules in a dose-dependent manner, although it did not influence cell proliferation using an MTT assay. This inhibitory effect depended upon the time at which activin-A was added to the culture media, and the effect was most significant when addition took place at the early phase of the culture. In addition, exogenous activin-A inhibited gene expression of type I procollagen, alkaline phosphatase, osteonectin, and osteopontin in the cultured cells using Northern blot analysis. The peak of osteocalcin mRNA was delayed. Gene expression for TGF-beta was not influenced by exogenous activin-A. The betaA subunit (activin-A) mRNA was detected during the early phase of this culture. These results indicate that activin-A inhibited early differentiation of the fetal rat calvarial cells, or osteoblasts.
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PMID:Inhibitory effects of activin-A on osteoblast differentiation during cultures of fetal rat calvarial cells. 1050 93

Numerous spontaneous and experimentally induced mouse mutations develop a hair phenotype, which is often associated with more or less discrete abnormalities in hair follicle development. In order to recognize these, it is critically important to be able to determine and to classify accurately the major stages of normal murine hair follicle morphogenesis. As an aid, we propose a pragmatic and comprehensive guide, modified after previous suggestions by Hardy, and provide a list of easily recognizable classification criteria, illustrated by representative micrographs. Basic and more advanced criteria are distinguished, the former being applicable to all mouse strains and requiring only simple histologic stains (hematoxylin and eosin, Giemsa, periodic acid Schiff, alkaline phosphatase activity), the latter serving as auxiliary criteria, which require a pigmented mouse strain (like C57BL/6J) or immunohistochemistry (interleukin-1 receptor type I, transforming growth factor-beta receptor type II). In addition, we present simplified, computer-generated schematic drawings for the standardized recording and reporting of gene and antigen expression patterns during hair follicle development. This classification aid serves as a basic introduction into the field of hair follicle morphogenesis, aims at standardizing the presentation of related hair research data, and should become a useful tool when screening new mouse mutants for discrete abnormalities of hair follicle morphogenesis (compared with the respective wild type) in a highly reproducible, easily applicable, and quantifiable manner.
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PMID:A comprehensive guide for the recognition and classification of distinct stages of hair follicle morphogenesis. 1050 36

Members of the transforming growth factor-beta (TGF-beta) superfamily, the bone morphogenetic and osteogenic proteins (BMPs/OPs) but not the TGF-beta proteins themselves, induce endochondral bone formation in vivo, when implanted in extraskeletal heterotopic sites of rodents. Here we show that recombinant human TGF-beta2 (hTGF-beta2) induces endochondral bone formation 30 days after implantation in heterotopic intramuscular sites of the baboon (Papio ursinus) at doses of 1, 5 and 25 microg per 100 mg of guanidinium-inactivated collagenous bone matrix as carrier. On day 90 there was generation of large radiopaque and corticalized intramuscular ossicles. Five and 25 microg hTGF-beta2 induced large ossicles in the rectus abdominis of the primate as evaluated by key parameters of bone formation, including generated tissue area, mineralized bone and osteoid volumes, and tissue alkaline phosphatase activity. On day 30 and 90 after healing, hTGF-beta2 also induced bone formation when implanted in the rectus abdominis in conjunction with a sintered porous hydroxyapatite as carrier. mRNA expression in tissues from heterotopic specimens showed OP-1 (BMP-7) and BMP-3 transcripts in low abundance and with a linear dose-dependent increase both in collagenous matrix and hydroxyapatite samples. Type IV collagen mRNA expression, a marker of angiogenesis, was stronger in collagenous than hydroxyapatite samples. Growth and differentiation factor-10 (GDF-10) mRNA transcripts were expressed in ossicles with a distinctly chondrogenic phase, but its expression was greater in ossicles generated in porous hydroxyapatites, in which bone formation is not via a chondrogenic phase, but is rather intramembranous, without expression of type II collagen mRNA. In the same animals, however, 10 and 100 microg of the recombinant morphogen delivered by identical carriers (collagenous matrix and sintered hydroxyapatite) failed to heal calvarial defects. Thus in the primate, TGF-betas themselves are inducers of endochondral bone formation, although the present data strongly indicate that the bone inductive activity of hTGF-beta2 is site and tissue specific, since a single application of hTGF-beta2, or hTGF-beta1 in previously published experiments, did not induce bone in calvarial defects, but did induce endochondral bone differentiation in heterotopic sites.
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PMID:Induction of endochondral bone formation by recombinant human transforming growth factor-beta2 in the baboon (Papio ursinus). 1151 29

Although transforming growth factor-beta (TGF-beta) is a growth factor with many known regulatory activities in many different cell types, its intracellular signaling pathway is still not fully understood. A TGF-beta-inducible early gene (TIEG) was discovered and shown by this laboratory to be a 3-zinc finger transcription factor family member; its expression is rapidly induced in cells treated with TGF-beta. To ascertain whether TIEG plays a major role in the TGF-beta pathway, human osteosarcoma MG-63 cells were stably transfected either with an expression vector containing a TIEG cDNA or with the vector alone. Clones that contain only the vector express normal levels of TIEG mRNA and protein and display the same patterns of gene expression and levels of cell proliferation as the nontransfected, non-TGF-beta-treated parental cells. However, transfected cells that overexpress TIEG mRNA and protein (TIEG-6 and TIEG-7) display changes that mimic those of MG-63 cells treated with TGF-beta, i.e. increased alkaline phosphatase activity, decreased levels of osteocalcin mRNA and protein, and decreased cell proliferation. The degree of these changes correlated with the level of TIEG expressed in the cell lines. TGF-beta treatment of the overexpressed cells showed no added effects. These findings and other published reports support a primary role of TIEG as a transcription factor in the TGF-beta signaling pathway.
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PMID:Overexpression of a nuclear protein, TIEG, mimics transforming growth factor-beta action in human osteoblast cells. 1081 51

Osteoarthritis is a degenerative joint disease characterized by destruction of the articular cartilage in aging and senescence. The aim of this study was to study the possible treatment of this disease by intraarticular injection of growth factors to osteoarthritic joints of aged animals. 20-month-old female ICR mice were injected with insulin-like growth factor (IGF-1), transforming growth factor-beta (TGF-beta) or TGF-beta+IGF-1 on days 1, 4, and 7. On day 9 the joints were dissected and cultured in the presence of 35S-sulfate and 3H-thymidine. Combined treatment of TGF-beta and IGF-1 resulted in elevated 3H-thymidine incorporation and DNA and protein contents, reduction of 35S-sulfate incorporation and alkaline phosphatase activity, with no significant change in the activity of acid phosphatase. Following injections of TGF-beta, contents of DNA and protein, and incorporations of 3H-thymidine were induced, and 35S-sulfate and alkaline phosphatase activity were reduced. Treatment with IGF-1 resulted in reduced incorporation of 3H-thymidine with no significant changes in the activity of acid phosphatase. Atypically hypertrophic chondrocytes were observed along the articular surface and the endogenous production of TGF-beta and of IGF-1, as revealed by immunohistochemistry, was reduced. It is concluded that although 3H-thymidine incorporation and alkaline phosphatase activity appeared to be induced by TGF-beta and IGF-1, the overall responsiveness of cartilage from aged mice to these growth factors appeared to be inhibitory. Moreover, their effects appeared to be limited to specific cell populations in the cartilage itself.
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PMID:Differential metabolic responses to local administration of TGF-beta and IGF-1 in temporomandibular joint cartilage of aged mice. 1109 Sep 10

Nitric oxide (NO) has been implicated in the local regulation of bone metabolism. However, the contribution made by specific NO synthase (NOS) enzymes is unclear. Here we show that endothelial NOS gene knockout mice (eNOS-/-) have marked abnormalities in bone formation. Histomorphometric analysis of eNOS-/- femurs showed bone volume and bone formation rate was reduced by up to 45% (P: < 0.01) and 52% (P: < 0.01), respectively. These abnormalities were prevalent in young (6 to 9 weeks old) adults but by 12 to 18 weeks bone phenotype was restored toward wild-type. Dual energy X-ray absorptiometry analysis confirmed the age-related bone abnormalities revealing significant reductions in femoral (P: < 0.05) and spinal bone mineral densities (P: < 0.01) at 8 weeks that were normalized at 12 weeks. Reduction in bone formation and volume was not related to increased osteoclast numbers or activity but rather to dysfunctional osteoblasts. Osteoblast numbers and mineralizing activity were reduced in eNOS-/- mice. In vitro, osteoblasts from calvarial explants showed retarded proliferation and differentiation (alkaline phosphatase activity and mineral deposition) that could be restored by exogenous administration of a NO donor. These cells were also unresponsive to 17ss-estradiol and had an attenuated chemotactic response to transforming growth factor-beta. In conclusion, eNOS is involved in the postnatal regulation of bone mass and lack of eNOS gene results in reduced bone formation and volume and this is related to impaired osteoblast function.
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PMID:Endothelial nitric oxide synthase gene-deficient mice demonstrate marked retardation in postnatal bone formation, reduced bone volume, and defects in osteoblast maturation and activity. 1114 98

Smad proteins are essential intracellular signal transducers of the transforming growth factor-beta (TGF-beta) superfamily. The TGF-beta superfamily signals through phosphorylation and activation of R-Smad proteins, receptor-regulated Smads, by heteromeric complexes of ligand-specific type I and type II serine/threonine kinase receptors. R-Smads receive a signal from the activated receptor complex and transmit it to the nucleus. A cDNA was isolated that encodes a 649-amino acid protein found to be homologous to members of R-Smad subfamily with highest homology scored to clawed African frog and human Smad2. The Schistosoma mansoni homologue (SmSmad2) was overexpressed in bacteria as a Sj26-GST fusion protein and used to raise specific antibodies. The IgG fraction of the immunized rabbit serum identified 70- and 72-kDa protein bands in Western analysis of schistosome extracts. Treatment with alkaline phosphatase removed the 72-kDa band, which indicates that this band represents the phosphorylated form of schistosome Smad2. SmSmad2 was localized in the subtegument, parenchymal cells, and sex organs in both male and female worm cryosections. Similar results were also obtained from the analysis of the Smad2 mRNA distribution pattern revealed by in situ hybridization of adult worm pair paraffin sections. SmSmad2 mRNA levels were determined by reverse transcriptase-polymerase chain reaction in different mammalian host developmental stages and found to be constitutively expressed. SmSmad2 was also found to interact with a previously identified SmTbetaR-I, a serine/threonine type I kinase receptor. Furthermore, SmSmad2 was shown to undergo phosphorylation by constitutively active forms of SmTbetaR-I in vitro. In addition, SmSmad2 localized in the nuclei of mink lung epithelial cells upon treatment with TGF-beta(1). These data indicate that the SmSmad2 responds to the TGF-beta signals by interaction with receptor I, which phosphorylates it, whereupon it translocates into the nucleus presumably to regulate target gene transcription and consequently elicit a specific TGF-beta effect.
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PMID:Identification and characterization of a Smad2 homologue from Schistosoma mansoni, a transforming growth factor-beta signal transducer. 1115 51

Uveal melanoma is the most common primary ocular cancer among adults and patients with distant metastases seldom survive longer than a year. Melanomas of the eye have the advantage of growing in the special environment of an immune privileged site and it has long been shown, that the special immunosuppressive properties of the intraocular microenvironment are strongly mediated by cytokines, especially transforming growth factor-beta (TGF-beta). Here, we sought to investigate the presence of TGF-beta in surgically removed uveal melanoma specimens using immunohistochemical methods to verify possible autocrine mechanisms. Immunocytochemistry for pan-TGF-beta and TGF-beta(2) was performed on 13 melanoma specimens using an alkaline phosphatase labeling procedure. Melanocytic origin of the tumors was confirmed by HMB-45 staining. All tissue samples exhibited positive staining using either pan-TGF-beta or TGF-beta(2) antibody regardless of cell-type, size of the tumor, or tumor location. The intensity of staining did not vary significantly within a given tumor. All tumors stained positive against the HMB-45 antibody. Many cytokines have been found to act on melanoma tumors. The presence of the TGF-beta(2) isoform in all specimens points to progressive tumor-growth as has been shown for melanomas of the skin. Based on our immunohistochemical findings and the immunosuppressive properties of TGF-beta, we suppose that ocular melanomas should be able to create their own immunosuppressive environment even in the uvea, which might be a non-privileged site.
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PMID:TGF-beta in uveal melanoma. 1117 Feb 98


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