Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gelatinases in inflammatory demyelinating diseases of the central nervous system (CNS) were studied using actively induced experimental autoimmune encephalomyelitis (EAE) in mice as a model system. Clinical disease scores correlated in time and in intensity with pathology parameters such as cytosis in the cerebrospinal fluid (CSF), inflammatory infiltrates, and demyelination in the CNS. Zymographic analysis was employed to measure gelatinases A and B in the CSF from individual animals. According to their apparent molecular weight (MW), gelatinases A and B appeared with a MW of 65 and 95 kDa, respectively. The 65 kDa form was present in all samples, even in those derived from non-induced animals, whereas the 95 kDa form was present only in samples from animals developing EAE. The levels of 95 and 65 kDa gelatinase correlated with the CSF cytosis. In vitro digestion of myelin basic protein (MBP) with gelatinase B and analysis of the cleavage products by protein sequence analysis pinpointed two cleavage sites in conserved regions of MBP. Gelatinase production within the CNS may constitute an important pathogenic mechanism for both the disruption of the blood-brain barrier and the destruction of myelin, as observed in several neuroinflammatory disorders.
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PMID:Gelatinase B is present in the cerebrospinal fluid during experimental autoimmune encephalomyelitis and cleaves myelin basic protein. 750 41

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

The role of extracellular proteolysis in inflammatory demyelination, originally hypothesized as a mechanism for myelin degradation, is increasingly recognized as a pathogenetic step and as a target for therapy in human demyelinating disease. The activation of ubiquitous plasminogen by urokinase (u-PA) and tissue-type plasminogen activator (t-PA), which is associated with various neuropathologies, including multiple sclerosis (MS), is the key initiator of the activation cascade of the four classes of matrix metalloproteinases (MMPs): collagenases, stromelysins, membrane-type metalloproteinases and gelatinases. Spatiotemporal protein and mRNA expression of gelatinase B (MMP-9) and matrilysin (MMP-7) have been documented respectively in MS lesions and in the central nervous system (CNS) of animals developing experimental autoimmune encephalomyelitis (EAE). A close interaction between disease-promoting cytokines and extracellularly acting proteases is deduced from in vitro experiments. Cytokines regulate the balance between the proteases and their respective specific inhibitors at the transcriptional level, while proteolysis is a reciprocal mechanism to enhance (by activation) or downmodulate (by degradation) the specific activities of cytokines. In acute inflammation the contribution of chemokines is hierarchically organised, interleukin-8 (IL-8) and related CXC-chemokines inducing a rapid influx of neutrophils in the acute lesions and an instantaneous exocytosis of gelatinase B granules. This results in sudden and extensive damage to the CNS. In chronic disease involving autoimmune processes CC-chemokines that act mainly on mononuclear cell types appear to be more strictly regulated. As MMPs modify matrix components, promoting extravasation of lymphocytes and monocytes/macrophages and have the potential to generate encephalitogenic peptides from myelin basic protein, novel treatments for demyelinating diseases may be predicted by specific inhibition of these enzymes. Here we review plasminogen activators and the MMP family, in the context of their role in CNS inflammation and demyelination and highlight studies in which intervention in these protease cascades are and may be used to treat demyelinating diseases.
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PMID:Plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system. 1037 31

Oligodendrocytes (OLs) extend processes to contact axons as a prerequisite step in myelin formation. As the OL processes migrate toward their axonal targets, they modify adhesion to their substrate, an event that may be regulated by matrix metalloproteinases (MMPs). In the mouse optic nerve, MMP-9/gelatinase B increases during myelin formation. Although tissue inhibitor of metalloproteinase (TIMP)-3 also increases in parallel, the developing optic nerve has focally active MMPs demonstrable by in situ zymography. The distribution of proteolytic activity is similar to that of myelin basic protein, a marker of myelin formation. OLs in culture secrete MMP-9 and express active cell-associated metalloproteinases at the growing tips of their processes. TIMP-1 and a function-perturbing anti-MMP-9 antibody attenuate outgrowth of processes by OLs, indicating a requirement for MMP-9 in process outgrowth. Process reformation is retarded significantly in OLs cultured from MMP-9 null mice, as compared with controls, providing genetic evidence that MMP-9 is necessary for process outgrowth. These data show that MMP-9 facilitates process outgrowth by OLs in vivo and in culture.
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PMID:Matrix metalloproteinase-9/gelatinase B is required for process outgrowth by oligodendrocytes. 1049 47

Gelatinase B (matrix metalloproteinase-9) is a secreted multidomain enzyme that is important for the remodeling of the extracellular matrix and the migration of normal and tumor cells. It cleaves denatured collagens (gelatins) and type IV collagen, which is present in basement membranes. In the immune system, this cleavage helps lymphocytes and other leukocytes to enter and leave the blood and lymph circulations. Gelatinase B also cleaves myelin basic protein and type II gelatins, and this clipping leads to remnant epitopes that generate autoimmunity, the so-called REGA model of autoimmunity. Recently, gelatinase B has been found to process cytokines and chemokines, resulting in skewed immune functions. Therefore, gelatinase B, often considered as a pure effector molecule, acts as a switch and catalyst in both innate and specific immunity, and constitutes a prototypic example of the regulation of immune functions by proteolysis.
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PMID:Gelatinase B: a tuner and amplifier of immune functions. 1157 82

Parenteral administration of interferon (IFN)-beta is one of the currently approved therapies for multiple sclerosis. One characteristic of this disease is the increased production of gelatinase B, also called matrix metalloproteinase (MMP) 9. Gelatinase B is capable of destroying the blood-brain barrier, and of cleaving myelin basic protein into immunodominant and encephalitogenic fragments, thus playing a functional role and being a therapeutic target in multiple sclerosis. Here we demonstrate that gelatinase B proteolytically cleaves IFN-beta, kills its activity, and hence counteracts this cytokine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN-beta-1b than with IFN-beta-1a. Furthermore, the tetracycline minocycline, which has a known blocking effect in experimental autoimmune encephalomyelitis, an in vivo model of acute inflammation in multiple sclerosis, and other MMP inhibitors prevent the in vitro degradation of IFN-beta by gelatinase B. These data provide a novel mechanism and rationale for the inhibition of gelatinase B in diseases in which IFN-beta has a beneficial effect. The combination of gelatinase B inhibitors with better and lower pharmacological formulations of IFN-beta may reduce the side-effects of treatment with IFN-beta, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections.
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PMID:Gelatinase B/matrix metalloproteinase-9 cleaves interferon-beta and is a target for immunotherapy. 1276 58

The aim of the study was to explore the effect of atorvastatin on improvement of the function of the spinal cord in rats with chronic fluorosis. Sixty 3-month-old Wistar rats were separated randomly into three groups: normal group (N group), control group (C group) and atorvastatin group (A group). The Basso Beattie and Bresnahan scale and oblique board test showed that the rats in A group got higher score and better hind-limb motor function than C group. Immunohistochemistry and western blotting revealed that compared with N group, matrix metalloproteinase 9 (MMP-9) and p53 were highly expressed and myelin basic protein (MBP) was low expressed in spinal cord of C group. Meanwhile, MMP-9 and p53 expression were decreased and MBP was upregulated by atorvastatin compared with C group. In conclusion, the improvement of the function of the spinal cord in rats can be found when they were treated with atorvastatin.
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PMID:Atorvastatin attenuates spinal cord injury by chronic fluorosis in rats. 3165 6