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:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been suggested that the trabecular meshwork may be involved in the pathogenesis of open-angle glaucoma, and some authors have pointed out that disorders of the extracellular matrix components may play a role; nevertheless, nothing is known about the normal metabolism of connective tissue molecules in this particular tissue. We recently initiated some studies in this field and have focused on the in vitro effects of aqueous humor on collagen metabolism. We report the finding of a latent collagenase of low molecular weight in aqueous humor obtained from cataractous patients; the enzyme was identified through several methods, including its in vitro activity against radiolabelled type I collagen and additionally with a zymogram technique. It was partially characterized by high-performance liquid chromatography.
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PMID:A latent collagenase in human aqueous humor. 253 47

Matrix metalloproteinase activity is the rate-limiting step in extracellular matrix degradation. One mechanism by which metalloproteinases are regulated is through the activity of their endogenous inhibitors, the tissue inhibitors of metalloproteinases. Since metalloproteinase activity is a key component of the angiogenic process and many anterior segment structures are largely avascular, we became interested in examining aqueous humor for the presence of metalloproteinases and their endogenous inhibitors. Using zymography, we have identified the presence of several metalloproteinases in normal aqueous humor. Treatment with 4-aminophenylmercuric acetate, an organomercurial which activates latent metalloproteinases, revealed that all metalloproteinases were in their active state. By Western blot analysis, normal aqueous humor was also found to contain at least two tissue inhibitors of metalloproteinases. Subsequent partial purification by two successive chromatographic steps revealed the presence of inhibitory activity against collagenase, endothelial cell DNA synthesis, and angiogenesis on the chick chorioallantoic membrane. The presence of metalloproteinases and their inhibitors in normal aqueous humor, a fluid which bathes avascular ocular structures, suggests that future studies should examine whether an imbalance in this protease/inhibitor family may contribute to the anterior chamber extracellular matrix alterations associated with diseases such as ocular neovascularization and glaucoma.
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PMID:Matrix metalloproteinases and their inhibitors in aqueous humor. 875 16

To investigate the distribution and potential participation of microglia, the resident defense cells of the central nervous system, in the optic nerve head (ONH) in glaucoma, histological paraffin sections of optic nerves from normal and glaucoma patients with mild to advanced nerve damage were studied using double labeling immunohistofluorescence. A monoclonal antibody for HLA-DR, indicating activated microglia, was colocalized with antibodies for functional proteins. In normal ONHs, microglia do not contain TGF-beta2, COX-2, or TNF-alpha and are not positive for PCNA; however, in glaucomatous ONHs, microglia contain abundant TGF-beta2, TNF-alpha, and PCNA. In glaucomatous eyes, a few microglia are usually positive for COX-2. In normal ONHs, there are rarely microglia containing TGF-beta1, NOS-2, TSP, TIMP-2, and CD68, but, in glaucomatous tissue, a few microglia are positive from the prelaminar to the postlaminar regions. MMP-1, MMP-2, MMP-3, and MMP-14 are constitutively present in the perivascular microglia in normal ONHs and appear to be more abundant in glaucomatous tissue. COX-1, TNF-R1, TIMP-1, and c-fms are constitutively present in normal tissues and appear to be increased in microglia in the glaucomatous ONHs. HSP27 is not present in microglia. In glaucomatous ONHs, microglia become activated and phagocytic and produce cytokines, mediators, and enzymes that can alter the extracellular matrix. Our findings suggest that activated microglia may participate in stabilizing the tissue early in the disease process, but, as the severity of the glaucomatous damage increases, the activities of microglia may have detrimental consequences for the pathological course of glaucomatous optic neuropathy.
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PMID:Activated microglia in the human glaucomatous optic nerve head. 1139 7

Excessive cell-mediated tissue contraction after injury can lead to morbid contractile scarring in the body. In the eye this can cause blindness because of posterior capsule opacification, proliferative vitroretinopathy, failure of glaucoma filtration surgery, and corneal haze. During repair, transforming growth factor (TGF)-beta and connective tissue growth factor (CTGF) genes are co-ordinately expressed. Although TGF-beta and CTGF stimulate new matrix deposition, their role and regulation during contractile scarring is unknown. In this study, an in vitro model of collagen matrix contraction culminating from tractional forces generated by fibroblasts showed that both TGF-beta(1) and CTGF-stimulated contraction. Using a specific anti-sense oligodeoxynucleotide to CTGF the procontractile activity of TGF-beta(1) was found to be mediated by CTGF. During contraction fibroblasts produced similar levels of matrix metalloproteinases (MMPs)-2 and -9 with TGF-beta(1) or CTGF and a modest increase in MMP-1 with CTGF only (indicated by zymography and enzyme-linked immunosorbent assay). The requirement of MMPs for contraction was demonstrated using a broad-spectrum synthetic inhibitor. This study demonstrates a new function for CTGF in mediating matrix contraction by fibroblasts involving MMPs and suggests a novel regulatory mechanism for TGF-beta-stimulated contraction. Inhibition of CTGF activity or gene transcription could be a suitable target for anti-scarring therapies.
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PMID:Mediation of transforming growth factor-beta(1)-stimulated matrix contraction by fibroblasts: a role for connective tissue growth factor in contractile scarring. 1457 3

Glaucoma is a common cause of blindness affecting at least 66 million people worldwide. Pigmentary glaucoma is one of the most common forms of secondary glaucoma, and its pathogenesis remains unclear. Interleukin-18 (IL-18) is an important regulator of innate and acquired immune responses and plays an important role in inflammatory/autoimmunity diseases. Using the DBA/2J mouse as an animal model of human pigmentary glaucoma, we demonstrated for the first time that the expression of the IL-18 protein and gene in the iris/ciliary body and level of IL-18 protein in the aqueous humor of DBA/2J mice are dramatically increased with age. This increase precedes the onset of clinical evidence of pigmentary glaucoma, implying a pathogenic role of inflammation/immunity in this disease. We also observed that activated NF-kappaB and phosphorylated MAPK are increased in the iris/ciliary body of DBA/2J mice, suggesting that both signaling pathways may be involved in IL-18 mediated pathogenesis of pigmentary glaucoma in the eyes of DBA/2J mice. In addition, matrix metalloproteinase-2 (MMP-2) expression in the iris/ciliary body and the activity of MMP-2 in the aqueous humor are increased whereas tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) expression in the iris/ciliary body is decreased, indicating that the degradation process is involved in this mouse model of pigmentary glaucoma. Furthermore, the expressions of apoptosis-related genes, caspase-8, Fas, FADD, FAP, and FAF, and the activity of caspase-3 are increased in the iris/ciliary body of DBA/2J mice. Elucidation of biochemical and molecular mechanisms of IL-18 participation in the pathogenesis of pigmentary glaucoma should provide approaches for developing improved and targeted treatments to ameliorate this blinding disease. The possibility that altered IL-18 expression in the eye of DBA/2J mice initiates and/or amplifies the pathogenesis of pigmentary glaucoma requires further investigation.
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PMID:Involvement of inflammation, degradation, and apoptosis in a mouse model of glaucoma. 1598 30

Prostaglandins (PGs) have been implicated in the regulation of intraocular pressure (IOP) by facilitating the remodeling of tissues involved in aqueous humor outflow. A contribution of cyclooxygenase-2 (COX-2)-dependent PGs to this process was emphasized by a recent study showing an impaired COX-2 expression in the nonpigmented ciliary epithelium (NPE) of patients with primary open-angle glaucoma. With the use of human NPE cells (ODM-2), the present study therefore investigated the effect of the antiglaucomatous drug latanoprost (PGF2alpha analog) on the expression of COX-2 and its association with the induction of matrix metalloproteinases (MMPs). In NPE cells, latanoprost led to a concentration- and time-dependent increase of COX-2 mRNA levels. Up-regulation of COX-2 expression was accompanied by phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK and was abrogated by specific inhibitors of both pathways. PGE2 formation by latanoprost was abolished by the selective COX-2 inhibitor NS-398 and by the F-prostaglandin receptor antagonist AL-8810. Moreover, latanoprost led to a delayed up-regulation of MMP-1 mRNA, whereas the expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 remained unchanged. Latanoprost-induced MMP-1 mRNA and protein expression was abolished by NS-398 and by COX-2-silencing small-interfering RNA. In line with this finding, MMP-1 expression was also induced by PGE2, a major COX-2 product. As a whole, our results show that MMP-1 expression by latanoprost requires prior up-regulation of COX-2. Induction of COX-2- and subsequent MMP-1 expression in the NPE may represent a potential mechanism underlying the IOP-lowering and antiglaucomatous action of latanoprost.
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PMID:Latanoprost induces matrix metalloproteinase-1 expression in human nonpigmented ciliary epithelial cells through a cyclooxygenase-2-dependent mechanism. 1607 63

Prostaglandins (PGs) and matrix metalloproteinases (MMP) have been implicated in lowering intraocular pressure (IOP) by facilitating aqueous humor outflow. A possible role of cyclooxygenase-2 (COX-2) in this process was emphasized by findings showing an impaired COX-2 expression in the nonpigmented ciliary epithelium (NPE) of patients with primary open-angle glaucoma. Using human NPE cells, the present study therefore investigated the effect of the IOP-lowering cannabinoid R(+)-methanandamide [R(+)-MA] on the expression of COX-2 and different MMPs and tissue inhibitors of MMPs (TIMPs). R(+)-MA led to a concentration- and time-dependent increase of COX-2 mRNA expression. R(+)-MA-induced COX-2 expression was accompanied by time-dependent phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK and was abrogated by inhibitors of both pathways. Moreover, R(+)-MA increased the mRNA and protein expression of MMP-1, MMP-3, MMP-9, and TIMP-1 but not that of MMP-2 and TIMP-2. Inhibition of COX-2 activity with NS-398 [N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide] was associated with a virtually complete suppression of R(+)-MA-induced MMP-9 and TIMP-1 expression. Consistent with these data, MMP-9 and TIMP-1 expression was also induced by PGE2, a major COX-2 product. Two other COX-2-inducing cannabinoids, anandamide and Delta9-tetrahydrocannabinol, caused the same pattern of MMP and TIMP expression as R(+)-MA both in the absence and presence of NS-398. Altogether, cannabinoids induce the production of several outflow-facilitating mediators in the human NPE. Our results further imply an involvement of COX-2-dependent PGs in MMP-9 and TIMP-1 expression. In conclusion, stimulation of intraocular COX-2 and MMP expression may represent a potential mechanism contributing to the IOP-lowering action of different cannabinoids.
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PMID:R(+)-methanandamide and other cannabinoids induce the expression of cyclooxygenase-2 and matrix metalloproteinases in human nonpigmented ciliary epithelial cells. 1633 Apr 97

Glaucoma is one of the most important civilization diseases and leads to irreversible blindness. Inspite of many years of research, the causes of this disorder remain unclear. This disease is extremely difficult to diagnose because its primary phase is asymptomatic. After laborious research it has been discovered that metalloproteinases, i.e. proteolytic enzymes involved in the pathogenesis of many kinds of glaucoma, are crucial in glaucoma diagnosis. The overexpression of matrixins leads to degradation of extracellular matrix components, which results in eye tissue injury and changes of tissue properties. Structural disorders occurring in this way are one of the many key reasons for progressive glaucomatous optic neuropathy. The presence of altered expressions of MMP-1, -2, -3, -7, -9, and -12 and their tissue inhibitors TIMP-1 and -2 in the glaucomatous eye paves new ways for the diagnosis and treatment of open-angle glaucoma. The detection of polymorphisms and mutations in genes encoding these enzymes will allow qualifying a patient to a risk group and people who are already ill may be treated by regulation of metalloproteinases activity. This review focuses on the presence and function of metalloproteinases in open-angle glaucoma and on treatment possibilities through MMP regulation.
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PMID:[Matrix metalloproteinases (MMPs): modern molecular markers of open-angle glaucoma diagnosis and therapy]. 1900 81

Failure of surgery for glaucoma is usually due to post-surgical scarring (fibrosis), a process in which fibroblasts play a prominent role. We investigated the molecular mechanisms of such scarring by examining the expression of matrix metalloproteinases and cytokines in Tenon fibroblasts isolated from rats after glaucoma surgery. Filtration surgery was performed in one eye and implant surgery in the other; and Tenon fibroblasts were isolated from the tissue surrounding the bleb after surgery. The cells were cultured and examined for the expression of matrix metalloproteinases (MMPs) by reverse transcription-polymerase chain reaction, immunoblot and gelatin zymographic analyses. Culture supernatants were also assayed for cytokines with a multiplex array. The amounts of MMP-1 and MMP-3 mRNAs and proteins were greater in cells isolated after implant surgery than in those isolated after filtration surgery, with the progression of scar formation being more complete after the former surgery. The secretion of interleukin-6 (IL-6) by cells isolated after filtration surgery was greater than that for cells isolated after implant surgery. Depletion of IL-6 by RNA interference in cells isolated after filtration surgery increased the expression of MMP-1 and MMP-3 in these cells. These results thus suggest that the expression of MMP-1 and MMP-3 in Tenon fibroblasts is regulated by IL-6 during, and may play an important role in, scar formation after glaucoma surgery.
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PMID:Matrix metalloproteinase and cytokine expression in Tenon fibroblasts during scar formation after glaucoma filtration or implant surgery in rats. 2308 31

Pseudoexfoliation syndrome (PXS) is a systemic condition with eye manifestations. In the eye, pseudoexfoliation material deposits on various structures of the anterior segment. The nature of this material is mostly fibrillar with fibers made up of microfibrils and coated with amorphous material. The composition of these fibrils is diverse and includes basement membrane components as well as enzymes involved in extracellular matrix maintenance. Pseudoexfoliation is the most common cause of secondary open-angle glaucoma (pseudoexfoliation glaucoma, PXG) worldwide. The goal of this review is to summarize our knowledge on the genetics of this systemic disorder and its resultant ocular manifestations. PXS familial aggregation suggests genetic inheritance. PXS has been strongly associated with single nucleotide polymorphisms (SNPs) of the lysyl oxidase-like 1 (LOXL1) gene on chromosome 15q24.1. Two of these SNPs confer a higher than 99% population attributable risk for PXS and PXG in the Nordic population; however, they carry different risks in different populations. The high risk haplotypes also vary among different populations. LOXL1 is one of group of the enzymes involved in the cross-linking of collagen and elastin in the extracellular matrix. Its function in connective tissue maintenance has been confirmed in mice; however, its actual role in PXS remains unclear. Contactin-associated protein-like 2 also has a strong genetic association with PXS in a German cohort and is an attractive candidate molecule. It encodes for a protein involved in potassium channel trafficking. Other candidate genes linked to PXS include lysosomal trafficking regulator, clusterin, adenosine receptors, matrix metalloproteinase-1 (MMP1), and glutathione transferase. These genes may be modifying genes for development of PXS and PXG.
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PMID:Pseudoexfoliation syndrome, a systemic disorder with ocular manifestations. 2315 66


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