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:3.4.24.35 (matrix metalloproteinase 9)
2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gelatinase B, a marker enzyme for chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis (MS), was found to cleave human myelin basic protein (MBP). Human MBP was digested with gelatinase B from leukocytes. The MBP peptide fragments were separated by RP-HPLC and the gelatinase B cleavage sites established by aminoterminal sequence analysis. Several novel P1-P1' cleavage sites for gelatinase B were found. The positions of the cleavage sites in human MBP were such that at least one peptide coincided with a documented major MBP-autoantigen. This study annotates human MBP as a substrate for human gelatinase B, determines novel P1-P'1 cleavage sites and defines one of the metalloproteinases as a possible link in the pathogenesis of demyelinating diseases such as MS.
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PMID:Leukocyte gelatinase B cleavage releases encephalitogens from human myelin basic protein. 768 61

Human gelatinase B was produced from peripheral blood neutrophils and purified by affinity chromatography on gelatin sepharose. This material was used as an antigen to prepare mouse monoclonal antibodies (mAb). The resulting hybridomas were selected on the basis of binding to biotinylated antigen and by a sandwich ELISA using gelatinase-B-specific polyclonal rabbit antiserum and pure natural antigen. Five of these mAb were selected for further characterization. They all displayed variable epitope specificity, binding capacity and inhibitory activity. Whereas mAb REGA-2D9 and REGA-3G12 showed the strongest binding to biotinylated gelatinase B and natural gelatinase B, respectively, mAb REGA-2F9 did not bind biotinylated antigen. None of the mAb displayed cross-reactivity to gelatinase A in a direct ELISA. The mAb REGA-1G8 was found to cross-react with human serum albumin. The binding capacity of the other four mAb with leukocyte gelatinase B was compared and a sensitive sandwich ELISA was developed with the antibodies REGA-3G12 and REGA-2D9 (detection limit 0.5 ng/ml). The mAb REGA-3G12 was unique in that it inhibited catalysis by gelatinase B. This was shown by assaying the degradation of nasal septum type II gelatin in the presence and absence of each of the five mAb. Furthermore, mAb REGA-3G12 inhibited the degradation of biotinylated gelatin in a microtiterplate solution assay. In addition to the potential use of the inhibitory mAb REGA-3G12 in the treatment of diseases with excessive gelatinase B production, several of the described mAb are useful as diagnostic probes to detect gelatinase B in body fluids and tissue samples of patients with multiple sclerosis, rheumatoid arthritis and cancer.
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PMID:Monoclonal antibodies specific for natural human neutrophil gelatinase B used for affinity purification, quantitation by two-site ELISA and inhibition of enzymatic activity. 857 32

A quantitative nonisotopic solution assay for gelatinases and inhibitors was developed using biotinylated gelatin as enzyme substrate. In this assay, residual biotinylated substrate is sandwiched between avidin-coated plates and streptavidin-peroxidase and is quantified by the peroxidase reaction. This assay was useful for measuring gelatinase activities and defining the activities of gelatinase inhibitors. When 23 tetracycline analogues were compared, significant differences in gelatinase B inhibition were found between various compounds. 4-epioxytetracycline base, 4-epichlortetracycline, meclocyclinesulfosalicylate, and unmodified metacycline and minocycline proved to be the most potent gelatinase B (EC 3.4.24.35) inhibitors. The gelatinase B inhibitory activity of tetracyclines was clearly dissociated from their antimicrobial activity. The effect of high-molecular-weight inhibitors, such as monoclonal antibodies, was also demonstrable in the microtiter plate assay. In view of the pathophysiological function of gelatinases, the definition of gelatinase inhibitors with known efficacy, safety, and side effects is crucial for the treatment of diseases such as rheumatoid arthritis and multiple sclerosis. Particular tetracyclines fulfil these criteria and the described assay is useful for defining other gelatinase-inhibiting lead compounds.
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PMID:The gelatinase inhibitory activity of tetracyclines and chemically modified tetracycline analogues as measured by a novel microtiter assay for inhibitors. 867 93

The in vitro activity of gelatinase B, an enzyme whose appearance in the cerebrospinal fluid is associated with inflammatory diseases of the central nervous system, was dose-dependently inhibited by the antirheumatic D-penicillamine. Inhibition of gelatinase B in electrophoretically pure preparations and in cell culture supernatants and human body fluids was obtained at dosages reached in the circulation of patients treated with a peroral dosis of 750 mg D-penicillamine per day. In mice, developing acute demyelination, D-penicillamine significantly reduced the mortality and morbidity rates of experimental allergic encephalomyelitis (EAE). In chronic relapsing EAE in Biozzi AB/H mice, an animal model for relapses in multiple sclerosis (MS), it attenuated the exacerbations, even when the treatment was started after the primary full-blown disease had developed. We infer protease inhibition as the mechanism of action of D-penicillamine and suggest that its use may be effective as peroral treatment for MS.
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PMID:Prevention of acute autoimmune encephalomyelitis and abrogation of relapses in murine models of multiple sclerosis by the protease inhibitor D-penicillamine. 878 33

The expression of tissue-type plasminogen activator (t-PA) and a number of metalloproteases as well as plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteases-1 (TIMP-1) was analyzed in the central nervous system (CNS) of normal control and multiple sclerosis (MS) cases by immunohistopathology. The expression of t-PA was detectable only in the blood vessel matrix in control white matter, but positive infiltrating mononuclear cells were also observed in MS white matter and primary lesions. In active plaques this pattern converted to strong positivity of foamy macrophages in areas of demyelination, declining in chronic lesions. In general PAI-1 expression paralleled that of t-PA. Gelatinase A and B were detected predominantly in astrocytes and microglia throughout normal control white matter, with additional positive mononuclear cells in perivascular cuffs in MS white matter. In the demyelinating lesion there is widespread prominent expression of gelatinase B in reactive astrocytes and macrophages, which persists in astrocytes in the chronic lesion. TIMP-1 was also present in the vessel matrix and in lesional macrophages. These observations on the coexpression of enzymes and inhibitors of the matrix degrading cascade in CNS tissue pinpoint t-PA, a rate-limiting enzyme, and gelatinase B as therapeutic targets in MS.
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PMID:The expression of tissue-type plasminogen activator, matrix metalloproteases and endogenous inhibitors in the central nervous system in multiple sclerosis: comparison of stages in lesion evolution. 895 42

The pathology of multiple sclerosis (MS) is characterised by breakdown of the blood-brain barrier accompanied by infiltration of macrophages and T cells into the central nervous system (CNS). Myelin is degraded and engulfed by the macrophages, producing lesions of demyelination. Some or all of these mechanisms might involve proteinases, and here we have studied the cellular localisation and distribution of two matrix metalloproteinases (MMPs), MMP-7 (matrilysin) and MMP-9 (92-kDa gelatinase), in the normal human CNS and active demyelinating MS lesions. Cryostat sections of CNS samples were immunostained with antisera to MMP-7 and MMP-9. In addition, non-radioactive in situ hybridisation (ISH) was performed using a digoxygenin-labelled riboprobe to detect the expression of MMP-7. MMP-7 immunoreactivity was weakly detected in microglial-like cells in normal brain tissue sections, and was very strong in parenchymal macrophages in active demyelinating MS lesions. This pattern of expression was confirmed using ISH. MMP-7 immunoreactivity was not detected in macrophages in spleen or tonsil indicating that it is specifically induced in infiltrating macrophages in active demyelinating MS lesions. MMP-9 immunoreactivity was detected in a few small blood vessels in normal brain tissue sections, whereas many blood vessels stained positive in CNS tissue sections of active demyelinating MS lesions. The up-regulation of MMPs in MS may contribute to the pathology of the disease.
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PMID:Enhanced expression of MMP-7 and MMP-9 in demyelinating multiple sclerosis lesions. 944 61

Human extracellular matrix is constantly remodelled by de novo synthesis of structural components and by degradation of the matrix proteins by various proteinases. The secreted proteolytic enzymes are regulated at several levels: by control of gene transcription, by glycosylation, by specific inhibitors and by enzyme activation processes. The latter level most often involves clipping of a proenzyme or zymogen into an active proteinase. A series of such activation reactions leads to enzyme cascades. Whereas proteolytic activation is an all-or-none phenomenon, glycosylation usually has a restricted or fine-tuning effect on the catalytic activity of enzymes. Commonly, a two- to threefold reduction in specific activity is imposed by N-glycosylation on each member of the multi-enzyme chain. In a series comprising e.g. four enzymes, this can lead to significant influences (2(4)-3(4)-fold increase) on the substrate converting activity of the terminal member of a cascade. Gelatinase B is a terminal member of the protease cascade which leads to matrix degradation. It cleaves gelatins (denatured collagens or collagen fragments after digestion by collagenase) and other substrates and is thought to be involved in matrix remodeling during the normal processes of embryogenesis, tissue remodeling and development. Gelatinase B expression is upregulated in pathological states such as invasion of cancer cells and when leukocytes are released from the bone marrow and migrate towards an inflammatory focus. Proteases, including gelatinase B, are transcriptionally regulated by cytokines and directly by the activation processes. The gene regulation of enzyme inhibitors as well as other humoral factors, which contribute to protease activation, influence protease activities in an indirect way. Proteases might also play a role in the pathophysiology of chronic inflammation and autoimmunity by cleaving extracellular structural proteins and by generating proteolytic fragments. Indeed, these remnant fragments antigenically resemble the original precursor proteins, but are structurally and quantitatively different and may provoke an autoimmune response. Application of the knowledge of the structure, function and regulation of gelatinase B has contributed to the understanding of the mechanism of action of some gelatinase-inhibiting antirheumatic drugs and promises to contribute further to the development of novel treatment strategies for autoimmune diseases such as multiple sclerosis and for invasive cancers.
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PMID:On the roles of extracellular matrix remodeling by gelatinase B. 954 20

Matrix metalloproteinases (MMPs) comprise a group of proteolytic enzymes that are implicated in the pathogenesis of inflammatory diseases of the nervous system such as multiple sclerosis. However, the exact function and expression pattern of MMPs in the inflamed nervous system are not known. In the present study we investigated the expression of 92-kDa gelatinase (MMP-9) in spinal cord from animals with adoptive transfer experimental autoimmune encephalomyelitis (AT-EAE), using a semiquantitative competitive reverse transcriptase-polymerase chain reaction assay. Increased levels of MMP-9 mRNA were found with peak values at times of maximum disease severity. Increased mRNA expression was associated with enhanced proteolytic activity of this enzyme, as demonstrated by gelatin zymography. Immunohistochemistry revealed immunoreactivity along the meninges, around blood vessels and within the parenchyma, in diseased but not in normal spinal cord. Furthermore, the expression pattern of five other MMPs was investigated. Matrilysin (MMP-7) was also found to be upregulated with maximum mRNA levels at the peak of the disease. In contrast, mRNAs for collagenase-3, 72-kDa gelatinase, and stromelysin-1 and -3 were not changed. Our findings indicate that 92-kDa gelatinase and matrilysin are selectively upregulated during AT-EAE and thus may contribute to the pathogenesis of inflammatory diseases of the CNS.
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PMID:Matrix metalloproteinase-9 and -7 are regulated in experimental autoimmune encephalomyelitis. 954 96

The serine proteinase tissue-type plasminogen activator (t-PA) and the metalloproteinase gelatinase B (MMP-9) have recently been demonstrated in MS lesions. Both enzymes are interconnected in an enzyme cascade which contributes to destruction of the blood brain barrier and demyelination and both enzymes are inhibited by D-penicillamine. Metacycline was shown in in vitro experiments to inhibit gelatinase B. The combination of peroral D-penicillamine plus metacycline was evaluated in a double-blind placebo-controlled way in two groups of 10 patients suffering from secondary progressive multiple sclerosis. The major objectives of this pilot trial were to examine the safety of this combination and the possibility of blinding, while the effect on disease progression was considered as a secondary endpoint. Over a follow-up period of 1 year and in this selected patient group, there was no significant improvement in the Expanded Disability Status Scale score (EDSS) as compared with that of the placebo-control group. Toxicity was too high to consider additional trials with this combination of metalloproteinase inhibitors. Although peroral treatment is by most MS patients acknowledged as a major improvement in treatment compliance, one has to await the development of more selective and efficacious protease inhibitors than those used in the combination therapy described here.
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PMID:Toxicity in a double-blind, placebo-controlled pilot trial with D-penicillamine and metacycline in secondary progressive multiple sclerosis. 959 37

Metalloproteinases have been implicated in the pathogenesis of multiple sclerosis. We report longitudinal serum levels of gelatinase B and of the tissue inhibitors of matrix metalloproteinases (TIMP), TIMP-1 and TIMP-2, in 21 patients with relapsing multiple sclerosis. Patients had monthly clinical and gadolinium-enhanced MRI follow-up for 10 months. Longitudinal samples in nine healthy controls and cross-sectional samples from 12 patients with inflammatory CNS disease and 15 patients with other neurological diseases were used for comparison. Average serum gelatinase B, TIMP-1 and TIMP-2 levels were significantly higher in multiple sclerosis patients and those with other neurological diseases than in healthy controls. In the patients with multiple sclerosis, gelatinase B levels were significantly higher during clinical relapse compared with periods of clinical stability. Multiple sclerosis patients with high mean serum gelatinase B levels had significantly more T1-weighted gadolinium-enhancing MRI lesions than those with mean levels within the control range. TIMP-1 levels were not different during relapse and between relapses. There was a trend for TIMP-2 levels to be lower during relapse compared with non-relapse periods. For similar levels of serum gelatinase B, associated TIMP-1 levels were significantly lower and TIMP-2 levels significantly higher in multiple sclerosis patients compared with the inflammatory CNS control group. We propose that an abnormality in the inhibitory response to metalloproteinases may play an aetiological role in the chronicity of multiple sclerosis.
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PMID:Serum gelatinase B, TIMP-1 and TIMP-2 levels in multiple sclerosis. A longitudinal clinical and MRI study. 1007 Oct 46


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