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 process of endochondral fracture healing is biochemically similar to growth plate calcification. Recent studies have identified potentially important roles for proteoglycan-degrading enzymes in the growth plate. The purpose of the study described herein was to identify, in healing fractures, neutral enzyme activities capable of degrading proteoglycans and other matrix proteins. Two sets of 60 male Sprague-Dawley rats underwent the production of closed femoral fractures. Calluses were retrieved at timed intervals, and cell and matrix vesicle fractions were prepared for electron microscopy, neutral peptidase, and alkaline phosphatase assays. In another group of 10 animals, fractions were prepared from 14-day calluses and examined for proteoglycanase activity. In the cell fractions, alkaline phosphatase, alanyl-beta-naphthylamidase, aminopeptidase, and endopeptidase activities showed somewhat parallel distributions peaking at approximately 14-17 days. In the matrix vesicle fractions, similar relative distributions were observed for alkaline phosphatase and endopeptidase. However, here the peak activities occurred up to 3 days later than they did in the cell fractions. Significant proteoglycanase activity was confirmed in both cell and matrix vesicle fractions. These findings are consistent with the hypotheses that (a) neutral peptidases, by virtue of their temporal expression in parallel with alkaline phosphatase, may be involved in preparing fracture callus matrix for calcification; and (b) matrix vesicles may convey certain of these enzymes to sites of both matrix degradation and calcification, since the same activities found in cells are found in matrix vesicles a few days later. The possibility that some of these enzymes are involved in growth factor activation remains to be investigated.
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PMID:Neutral protein-degrading enzymes in experimental fracture callus: a preliminary report. 267 85

To more clearly define the expression of metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) within the human osteoblast (hOB) lineage, normal hOB and human osteogenic sarcoma cells possessing various levels of alkaline phosphatase (a marker of commitment to the osteoblast lineage) were treated with bone-resorbing agents to determine their effect on the production of interstitial collagenase, stromelysin, 72-kilodalton (kDa) gelatinase, 92-kDa gelatinase, TIMP-1, and TIMP-2. The results revealed that 1) normal hOB release copious amounts of 72-kDa gelatinase, TIMP-1, and TIMP-2; 2) hOB production of 72-kDa gelatinase and TIMP-2 is not regulated by agents that promote bone resorption (e.g. phorbol-12-myristate 13-acetate, recombinant human interleukin-1 beta, tumor necrosis factor-alpha, PTH, and vitamin D3); 3) normal hOB fail to secrete collagenase, stromelysin, or 92-kDa gelatinase when cultured on plastic or a type I collagen substratum, even in response to bone-resorptive agents or mononuclear cell-conditioned medium; 4) in contrast, certain of the osteogenic sarcoma cell populations produce collagenase, stromelysin, and 92-kDa gelatinase, especially when exposed to bone-resorbing stimuli; 5) in general, the capacity for metalloenzyme production by osteogenic sarcoma cell lines varies inversely with their alkaline phosphatase expression; and 6) the most committed (highest alkaline phosphatase) osteogenic sarcoma cell line, SAOS-2, precisely mimics the metalloproteinase profile of normal hOB. The results suggest that the expression of most metalloproteinases is under strict repression within the differentiated normal hOB, and cellular development is associated with diminished capacity to elaborate such enzymes.
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PMID:Expression of metalloproteinases and tissue inhibitors of metalloproteinases in human osteoblast-like cells: differentiation is associated with repression of metalloproteinase biosynthesis. 827 36

The temporo-mandibular joint of aged mice develops osteoarthritic (OA) degenerative lesions. Adult chondrocytes have a low rate of cell replication, and cartilage repair potential is very limited. One of the major problems in OA is the low rate of matrix synthesis and the inability of the chondrocytes to exceed the rate of matrix degradation. These combined factors lead to the overall destruction of the cartilage as seen in OA. Cartilage degradation is mediated by elevated proteolytic activity of enzymes. Among the enzymes degrading cartilage are the metalloproteinases, stromelysin and collagenase. Other proteinases that may potentially participate in matrix degradation are the lysosomal enzymes cathepsin B, D, and L, and acid phosphatase. On the other hand, alkaline phosphatase (ALP) is an enzyme that has been shown to be a marker for anabolic activity in skeletal tissues such as bone and cartilage. The cartilage of the mandibular condyle in the T-M-J from aged mice reveals OA lesions. An overall reduction of cell proliferation and sulfated proteoglycan synthesis has been also shown in this joint. In the present study the effects of hTGF-beta on the stimulation of DNA and sulfated GAG synthesis and ALP activity were studied. Mandibular condyle cartilage obtained from 12-month-old ICR male mice were cultured in BGJb serum-free medium for 24-72 hours, supplemented with 0.1-10 ng/ml hTGF-beta 1. 3H-thymidine and 35S-sulfate were added for the last 24 hours of the culture and their incorporation into DNA and sulfated GAGs respectively, as well as the activity of ALP, were determined. Results indicated that hTGF-beta 1 enhanced the incorporation of both 3H-thymidine and of 35S-sulfate into cartilage cultures of aged mice, and also induced ALP activity. It thus appeared that in OA degenerating articular cartilage, the chondrocytes could be stimulated in vitro to proliferate and to synthesize new matrix, thus indicating induced anabolic activity in the tissue.
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PMID:Osteoarthritis in the temporo-mandibular joint (TMJ) of aged mice and the in vitro effect of TGF-beta 1 on cell proliferation, matrix synthesis, and alkaline phosphatase activity. 918 53

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is synthesized as a membrane-anchored precursor that is cleaved to release the soluble mature growth factor. The two forms are active as juxtacrine and paracrine/autocrine growth factors, respectively. The enzymes that process the HB-EGF transmembrane form are unknown. Accordingly, an in vitro assay was established using a fusion protein in which alkaline phosphatase (AP) replaced the transmembrane and cytoplasmic domains of HB-EGF (HB-EGF JM-AP). The fusion protein was anchored to agarose beads coated with anti-AP antibodies. Several matrix metalloproteinases (MMPs) were tested for the ability to release soluble HB-EGF in the in vitro system. MMP-3 released soluble 12-kDa immunoreactive and mitogenic HB-EGF within 30 min. On the other hand neither MMP-2 nor MMP-9 had any cleavage activities. A non-cleavable mutant was prepared by replacing the juxtamembrane (JM) region of HB-EGF with the JM region of CD4. The mutant HB-EGF, which in its full-length form was as active a juxtacrine growth factor as was the wild type HB-EGF in vivo, was not cleaved by MMP-3 in the in vitro assay. The C-terminal portion of the cleaved HB-EGF JM-AP that remained attached to the anti-AP beads was N-terminally sequenced and the MMP-3 cleavage site was determined to be Glu151-Asn152, a site within the JM domain. MMP-3 treatment also released soluble HB-EGF in vivo from MC2 cells expressing transmembrane HB-EGF precursor, at a level of about 2-fold above control. It was concluded that MMP-3 cleaves HB-EGF at a specific site in the JM domain and that this enzyme might regulate the conversion of HB-EGF from being a juxtacrine to a paracrine/autocrine growth factor.
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PMID:Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site. 939 17

Structural changes in the extracellular matrix (ECM) are necessary for cell migration during tissue remodeling and local neoplastic cell invasion. The matrix metalloproteinases (MMPs) and their inhibitors have been shown to be critical modulators of ECM composition and are thus, crucial in tumor cell invasion and metastasis. The immunocytochemical profile of MMP-2, -3, -9, -10, and -13 expression was observed in 24 primary human childhood astrocytomas (ASTRs) employing an indirect alkaline phosphatase conjugated antigen detection technique. Evaluation of the results was based on (a) the percent of neoplastically transformed cells that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D (negative)]. The two forms of stromelysin, MMP-3 and -10, share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found in ASTRs, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells (+4) and the staining intensity was also the strongest possible (A,B). No immunoreactivity was detected using antibodies directed against MMP-2, -9, and -13. Based on these results, MMP-3 and -10 are implicated in the pathogenesis of pediatric ASTRs. Further characterization of the expression and utilization of MMPs and their inhibitors in the progression of ASTRs may establish differential regulation and utilization of the various MMPs during the progression of glial tumors, from low-grade pilocytic ASTR to high-grade glioblastoma multiforme.
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PMID:Matrix metalloproteinase expression in childhood astrocytomas. 1106 55

Structural changes in the extracellular matrix (ECM) are necessary for cell migration during tissue remodeling and tumor invasion. The matrix metalloproteinases (MMPs) and their inhibitors have been shown to be critical modulators of ECM composition and are thus crucial in neoplastic cell invasion and metastasis. Expression of MMP-2, -3, -9, -10, and -13 was investigated in human hepatocellular carcinomas (HCCs) employing an indirect alkaline phosphatase conjugated immunocytochemical technique. Evaluation of the results was based on (a) the persent of neoplastically transformed cells/surrounding stroma that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D]. The two forms of stromelysin, MMP-3 and -10, share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found in HCCs, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells (++++), and the staining intensity was also the strongest possible (A,B). No immunoreactivity was detected using antibodies directed against MMP-2, -9, and -13.
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PMID:Immunocytochemical detection of MMP-3 and -10 expression in hepatocellular carcinomas. 1121 Aug 57

Matrix metalloproteinases (MMP) are a family of zinc-dependent enzymes which degrade various components of the extracellular matrix (ECM) and play an important role in facilitating neoplastic cell invasion and metastasis. Structural changes in the extracellular matrix are necessary for cell migration during tissue remodeling and tumor invasion. Expression of MMP-2, -3, -9, -10, and -13 was investigated in both spontaneous and xenografted (cells derived from an established cell-line [DAOY#3]) childhood medulloblastomas (MEDs)/primitive neuroectodermal tumors (PNETs) employing an indirect alkaline phosphatase conjugated immunocytochemical technique. Evaluation of the results was based on (a) the percent of neoplastically transformed tissue that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D]. The two forms of stromelysin (SL), types 1 (MMP-3) and 2 (MMP-10), share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found only in the spontaneous MEDs/PNETs, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells in the spontaneous cases, and the staining intensity was also the strongest possible (A,B). Focal (surrounding less than 10% of the neoplastically transformed cells) but strong (A,B) immunoreactivity for collagenase-3 (MMP-13) was also only detected in spontaneous MEDs/PNETs, an endopeptidase characterized by a potent degrading activity against a wide spectrum of substrates. Weak (surrounding anywhere between 10% and 90% of the neoplastically transformed cells, and of B and B,C intensity) expression of MMP-2 (gelatinase A) and MMP-9 (gelatinase B), two cytokine-induced MMPs, was also observed in the spontaneous cases. Staining for MMP-2 was negative in the xenografted MEDs/PNETs. The only positive immunoreactivity in the xenografted MEDs/PNETs was observed in the case of MMP-9, with expression of strong intensity in the ECM surrounding over 90% of the neoplastically transformed xenografted MED/PNET cells (++++; A,B). It is clear that the activation of MMPs and their inhibitors occurs in a very well orchestrated manner. The data presented here suggest that there are significant differences in the pathophysiology of spontaneous and xenografted human neoplasms, which further establishes the already detected limitations of such models in preclinical cancer research.
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PMID:Significant differences in the matrix metalloproteinase expression profiles of spontaneous medulloblastomas/primitive neuroectodermal tumors as compared with their xenografted, established tumor cell line derived counterparts. 1121 45

The matrix metalloproteinases (MMPs) are a family of enzymes that degrade the extracellular matrix (ECM) and are considered to be important in neoplastic cell invasion and metastasis. Structural changes in the extracellular matrix are necessary for cell migration during tissue remodeling and neoplastic invasion. Expression of MMP-2, -3, -9, -10, and -13 was investigated in human childhood medulloblastomas (MEDs)/primitive neuroectodermal tumors (PNETs) employing an indirect alkaline phosphatase conjugated immunohistochemical antigen detection technique. Evaluation of the results was based on (a) the percent of neoplastically transformed tissue that reacted positively and (b) a measure of immunoreactivity or staining intensity [graded from A (highest) to D (negative)]. Strong overall expression of MMP-3 and -10 was found in MEDs/PNETs, especially in the ECM adjacent to blood vessels. Positive immunoreactivity was identified for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells with the staining intensity being also the strongest possible (A,B). These two forms of stromelysin (SL), types 1 (MMP-3) and 2 (MMP-10), share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Focal (surrounding less than 10% of the neoplastically transformed cells) but strong (A,B) immunoreactivity was determined for collagenase-3 (MMP-13), an endopeptidase characterized by a potent degrading activity against a wide spectrum of substrates. Weak (surrounding anywhere between 10% and 90% of the neoplastically transformed cells, and of B and B,C intensity) expression of MMP-2 (gelatinase A) and MMP-9 (gelatinase B), two cytokine-induced MMPs, was also observed. It is clear that the activation of MMPs and their inhibitors occurs in a very well orchestrated manner. The necessity of these same enzymes for the extravasation and infiltration of lymphocytes into regions of chronic local inflammation, as associated with neoplastically transformed masses of cells, may aid the transformed cells which have already acquired a more aggressive, metastatic immunophenotype (IP) to enter the peripheral circulation. Further characterization of the expression and utilization of MMPs and their inhibitors in the progression of solid human malignancies should lead to the development of novel anti-cancer therapies.
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PMID:Matrix metalloproteinase expression in childhood medulloblastomas/primitive neuroectodermal tumors. 1121 44

The matrix metalloproteinases (MMPs) are a family of enzymes that degrade the extracellular matrix (ECM) and are considered to be important in neoplastic cell invasion and metastasis. Structural changes in the extracellular matrix are necessary for cell migration during tissue remodeling and neoplastic cell invasion. Histochemical expression of MMP-2, -3, -9, -10, and -13 was observed in 19 human colorectal carcinomas (CCs) employing an indirect alkaline phosphatase (AP) conjugated antigen detection technique. Evaluation of the results was based on (a) the percent of neoplastically transformed cells that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D]. The two forms of stromelysin (SL), types 1 (MMP-3) and 2 (MMP-10), share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found in all CC cases observed, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells, and the staining intensity was also the strongest possible (A,B). Weak (surrounding anywhere between 10% and 90% of the neoplastically transformed cells, and of strong A,B intensity) expression of MMP-2 (gelatinase A) and MMP-9 (gelatinase B), two cytokine-induced MMPs, was also observed in CCs. Expression of collagenase-3 (MMP-13), an endopeptidase characterized by a potent degrading activity against a wide spectrum of substrates, was not defined in the CCs cases observed by us. It is clear that the activation of MMPs and their inhibitors occurs in a very well orchestrated manner. The necessity of these same enzymes for the extravasation and infiltration of lymphocytes into regions of chronic local inflammation, as associated with neoplastically transformed masses of cells, may aid the transformed cells which have already acquired a metastatic immunophenotype to enter the peripheral circulation. Further characterization of the expression and utilization of MMPs and their inhibitors in the progression of solid human neoplasms should lead to the development of novel anti-cancer therapies.
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PMID:Prognostic significance of matrix metalloproteinase expression in colorectal carcinomas. 1121 43

Structural changes in the extracellular matrix (ECM) are necessary for cell migration during tissue remodeling and tumor invasion. The matrix metalloproteinases (MMPs) and their inhibitors have been shown to be critical modulators of ECM composition and are, thus, crucial in neoplastic cell invasion and metastasis. Expression of MMP-2, -3, -9, -10, and -13 was investigated in human malignant melanomas (MMs) employing an indirect alkaline phosphatase conjugated immunocytochemical technique. Evaluation of the results was based on (a) the percent of neoplastically transformed cells/surrounding stroma that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D]. The two forms of stromelysin, MMP-3 and -10, share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found in MMs, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells (++++), and the staining intensity was also the strongest possible (A,B). Focal (+), high intensity (A,B) staining could be detected for MMP-2, -9, and -13. Thus, it seems that the stromelysins are involved in the generalized growth and expansion of the neoplastic cell mass, while MMP-2, -9 and -13 are involved in the neoangiogenic and focal clonal selection and expansion phenomena associated with in situ tumor progression, invasion of the microvasculature, and metastasis.
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PMID:Matrix metalloproteinase expression in malignant melanomas: tumor-extracellular matrix interactions in invasion and metastasis. 1128 31


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