Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased activity of matrix metalloproteinases (MMPs) has been implicated in numerous disease processes, including tumor growth and metastasis, arthritis, and periodontal disease. It is now becoming increasingly clear that extracellular matrix degradation by MMPs is also involved in the pathogenesis of cardiovascular disease, including atherosclerosis, restenosis, dilated cardiomyopathy, and myocardial infarction. Administration of synthetic MMP inhibitors in experimental animal models of these cardiovascular diseases significantly inhibits the progression of, respectively, atherosclerotic lesion formation, neointima formation, left ventricular remodeling, pump dysfunction, and infarct healing. This review focuses on the role of MMPs in cardiovascular disease, in particular myocardial infarction and the subsequent progression to heart failure. MMPs, which are present in the myocardium and capable of degrading all the matrix components of the heart, are the driving force behind myocardial matrix remodeling. The recent finding that acute pharmacological inhibition of MMPs or deficiency in MMP-9 attenuates left ventricular dilatation in the infarcted mouse heart led to the proposal that MMP inhibitors could be used as a potential therapy for patients at risk for the development of heart failure after myocardial infarction. Although these promising results encourage the design of clinical trials with MMP inhibitors, there are still several unresolved issues. This review describes the biology of MMPs and discusses new insights into the role of MMPs in several cardiovascular diseases. Attention will be paid to the central role of the plasminogen system as an important activator of MMPs in the remodeling process after myocardial infarction. Finally, we speculate on the use of MMP inhibitors as potential therapy for heart failure.
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PMID:Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? 1148 70

Overexpression of interleukin (IL-)17 has recently been shown to be associated with a number of pathological conditions. Because IL-17 is found at high levels in the synovial fluid surrounding cartilage in patients with inflammatory arthritis, the present study determined the direct effect of IL-17 on articular cartilage. As shown herein, IL-17 was a direct and potent inducer of matrix breakdown and an inhibitor of matrix synthesis in articular cartilage explants. These effects were mediated in part by leukemia inhibitory factor (LIF), but did not depend on interleukin-1 activity. The mechanism whereby IL-17 induced matrix breakdown in cartilage tissue appeared to be due to stimulation of activity of aggrecanase(s), not matrix metalloproteinase(s). However, IL-17 upregulated expression of matrix metalloproteinase(s) in chondrocytes cultured in monolayer. In vivo, IL-17 induced a phenotype similar to inflammatory arthritis when injected into the intra-articular space of mouse knee joints. Furthermore, a related protein, IL-17E, was found to have catabolic activity on human articular cartilage. This study characterizes the mechanism whereby IL-17 acts directly on cartilage matrix turnover. Such findings have important implications for the treatment of degenerative joint diseases such as arthritis.
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PMID:Pathways by which interleukin 17 induces articular cartilage breakdown in vitro and in vivo. 1166 82

The collagenases of the matrix metalloproteinase family are key enzymes in mediating irreversible cartilage collagen loss in arthritis. Inhibition of these enzymes is, therefore, an important therapeutic target. New approaches to collagenase inhibition include active site inhibitors designed for specific enzymes, inhibition of cell signalling molecules and transcription factors involved in collagenase gene expression, prevention of zymogen activation and induction of natural inhibitor production.
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PMID:The inhibition of metalloproteinases as a therapeutic target in rheumatoid arthritis and osteoarthritis. 1171 57

Recent work has established that IL-1beta plays a central role in the inflammation and connective tissue destruction observed in both rheumatoid arthritis and osteoarthritis. These processes result from the ability of this inflammatory cytokine to activate expression of genes for neutral proteases, such as the matrix metalloproteinases. While IL-1beta activates matrix metalloproteinase genes within several hours, it also activates immediate early genes, which are required for the later expression of matrix metalloproteinases and other arthritis-perpetuating genes, are also activated. To identify putative immediate early genes involved in IL-1beta-mediated arthritic disease, a chondrocytic cell line (SW1353) was stimulated with this cytokine for 2 hours, total RNA was isolated, and expressed genes were identified by microarray analysis. This analysis identified alterations in the expression of multiple transcription factors, cytokines, growth factors and their receptors, adhesion molecules, proteases, and signaling intermediates that may contribute to inflammation and cartilage destruction in arthritis. Interestingly, confirmation of the expression of activating protein-1 family members by reverse transcriptase polymerase chain reaction revealed a preferential increase in junB, a known transcriptional antagonist of c-jun. The failure to observe induction of early growth response gene-1, which was detected by reverse transcriptase polymerase chain reaction to be substantially and transiently induced by 1 hour of IL-1 treatment, may be explained by the known instability of the message after early induction. However, this analysis has identified numerous IL-1beta-responsive genes that warrant further investigation as mediators of disease in arthritis.
Arthritis Res 2001
PMID:Early response genes induced in chondrocytes stimulated with the inflammatory cytokine interleukin-1beta. 1171 93

Angiogenesis is a prominent feature of numerous diseases, including cancer and arthritis, and appears to play an important role in kidney disease and hypertension. The matrix metalloproteinases, especially matrix metalloproteinase-2, play a vital role during angiogenesis by degrading the surrounding extracellular matrix and allowing endothelial cell invasion. Membrane type 1 matrix metalloproteinase directly degrades matrix components as well as activating matrix metalloproteinase-2 on the cell surface. The integrin receptors, particularly alpha(v)beta(3), can recruit and possibly activate matrix metalloproteinases to localized microdomains on the cell membrane. This restricts matrix metalloproteinase activity to the pericellular region, preventing excessive matrix degradation which would otherwise impede endothelial invasion. Inhibitors of matrix metalloproteinase activity may actually promote cell invasion by preventing uncontrolled matrix degradation. In addition to degrading the matrix, matrix metalloproteinases produce protein fragments that impede their angiogenic action. These multiple regulatory pathways permit fine control over cell invasion during angiogenesis and provide new, precise strategies for targeting abnormal angiogenesis, through control of matrix metalloproteinase activity.
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PMID:Matrix metalloproteinases and angiogenesis. 1198 Dec 59

Fragments of fibronectin occur naturally in vivo and are increased in the synovial fluid of arthritis patients. We have studied the 45 kDa fragment (Fn-f 45), representing the N-terminal collagen-binding domain of fibronectin, for its ability to modulate the expression of metalloproteinases by porcine articular chondrocytes in vitro. We report that stimulation of cultured chondrocytes, or cartilage explants, with Fn-f 45 increased the levels of matrix metalloproteinase-13 (MMP-13; collagenase-3) released into the conditioned medium in a dose-dependent manner. Increased levels of MMP-13 were due to stimulation of MMP-13 synthesis, rather than release of MMP-13 from accumulated matrix stores. Fn-f 45 also stimulated the synthesis of MMP-3 (stromelysin-1) from cultured chondrocytes and cartilage cultures. The Fn-f 45-induced increase in MMP-3 and MMP-13 synthesis occurred via an interleukin 1-independent mechanism, since the receptor antagonist of interleukin-1 was unable to block the increased synthesis. The gelatinases, MMP-2 and MMP-9, were not modulated by Fn-f 45 in these culture systems. Fn-f 45 also stimulated the release of aggrecan from cartilage explants into conditioned medium. Neoepitope antibodies specific for aggrecan fragments generated by MMPs or aggrecanases showed that the Fn-f 45-induced aggrecan loss was mediated by aggrecanases, and not by MMPs. Extracts of cultured cartilage contained elevated levels of the aggrecanase-derived ITEGE(373)-G1 domain, whereas levels of the matrix metalloproteinase-derived DIPEN(341)-G1 domain were unchanged. These studies show that Fn-f 45 can induce a catabolic phenotype in articular chondrocytes by up-regulating the expression of metalloproteinases specific for the degradation of collagen and aggrecan.
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PMID:The 45 kDa collagen-binding fragment of fibronectin induces matrix metalloproteinase-13 synthesis by chondrocytes and aggrecan degradation by aggrecanases. 1198 91

Several matrix metalloproteinases (MMPs), including MMP-1, -3, and -9, mediate matrix destruction during chronic inflammatory diseases such as arthritis and atherosclerosis. MMP up-regulation by inflammatory cytokines involves interactions between several transcription factors, including activator protein-1 and nuclear factor kappaB (NF-kappaB). The upstream regulatory pathways are less well understood. We investigated the role of isoforms of protein kinase C (PKC) in basic fibroblast growth factor- and interleukin-1alpha-mediated MMP production from cultured rabbit aortic smooth muscle cells. A synthetic PKC inhibitor, RO318220, inhibited MMP-1, -3, and -9 production by 89 +/- 3, 75 +/- 18, and 89 +/- 9%, respectively. However, down-regulation of conventional and novel isoforms did not inhibit but rather increased MMP-9 production by 48 +/- 16%, implicating an atypical PKC isoform. Consistent with this, PKCzeta protein levels and activity were stimulated 3.3- and 13-fold, respectively, by basic fibroblast growth factor plus interleukin-1alpha and antisense oligonucleotides to PKCzeta significantly decreased MMP-9 formation by 62 +/- 18% compared with scrambled sequences. Moreover, adenovirus-mediated overexpression of a dominant-negative (DN) PKCzeta reduced MMP-1, -3, and -9 production by 78 +/- 9, 76 +/- 8, and 76 +/- 5%, respectively. DN-PKCzeta inhibited NF-kappaB DNA binding but did not affect ERK1/2 activation or AP-1 binding. Antisense PKCzeta oligonucleotides and DN-PKCzeta stimulated cell proliferation by 89 +/- 14% (n = 4) and 305 +/- 74% (n = 3), respectively (both p < 0.05). Our results show that PKCzeta is essential for cytokine-induced up-regulation of MMP-1, -3, and -9, most likely by activating NF-kappaB. Selective inhibition of PKCzeta is therefore a possible strategy to inhibit MMP production in inflammatory diseases such as atherosclerosis.
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PMID:Activation of protein kinase Czeta is essential for cytokine-induced metalloproteinase-1, -3, and -9 secretion from rabbit smooth muscle cells and inhibits proliferation. 1200 Jul 46

We have recently found that matrix metalloproteinases (MMPs) are targets for T-cell and B-cell reactivity in experimental arthritis. In the present article, we investigate whether modulation of MMP-specific T-cell responses could influence the course of adjuvant arthritis (AA). Lewis rats were treated nasally with MMP peptides prior to or after AA induction. Administration of the MMP-10 or the MMP-16 peptide prior to AA induction reduced the arthritic symptoms. In contrast, administration of the MMP-10 peptide after AA induction aggravated the arthritic symptoms. The present study shows the possible usefulness of MMP peptides for immunotherapy. However, a clear understanding of proper timing of peptide administration is crucial for the development of such therapies.
Arthritis Res 2002
PMID:Successful immunotherapy with matrix metalloproteinase-derived peptides in adjuvant arthritis depends on the timing of peptide administration. 1210 1

The role of matrix metalloproteinases in the degradative events invoked in the cartilage and bone of arthritic joints has long been appreciated and attempts at the development of proteinase inhibitors as potential therapeutic agents have been made. However, the spectrum of these enzymes orchestrating connective tissue turnover and general biology is much larger than anticipated. Biochemical studies of the individual members of the matrix metalloproteinase family are now underway, ultimately leading to a more detailed understanding of the function of their domain structures and to defining their specific role in cellular systems and the way that they are regulated. Coupled with a more comprehensive and detailed study of proteinase expression in different cells of joint tissues during the progress of arthritic diseases, it will be possible for the future development and application of highly specific proteinase inhibitors to be directed at specific key cellular events.
Arthritis Res 2002
PMID:Matrix metalloproteinases in arthritic disease. 1271 40

Tissue inhibitors of metalloproteinases (TIMPs) are the major cellular inhibitors of the matrix metalloproteinase (MMP) sub-family, exhibiting varying efficacy against different members, as well as different tissue expression patterns and modes of regulation. Other proteins have modest inhibitory activity against some of the MMPs, including domains of netrins, the procollagen C-terminal proteinase enhancer (PCPE), the reversion-inducing cysteine-rich protein with Kazal motifs (RECK), and tissue factor pathway inhibitor (TFPI-2), but their physiological significance is not at all clear. Alpha2-macroglobulin, thrombospondin-1 and thrombospondin-2 can bind to some MMPs and act as agents for their removal from the extracellular environment. In contrast, few effective inhibitors of other members of the metzincin family, the astacins or the distintegrin metalloproteinases, ADAMs have been identified. Many of these MMP inhibitors, including the TIMPs, possess other biological activities which may not be related to their inhibitory capacities. These need to be thoroughly characterized in order to allow informed development of MMP inhibitors as potential therapeutic agents. Over activity of MMPs has been implicated in many diseases, including those of the cardiovascular system, arthritis and cancer. The development of synthetic small molecule inhibitors has been actively pursued for some time, but the concept of the use of the natural inhibitors, such as the TIMPs, in gene based therapies is being assessed in animal models and should provide useful insights into the cell biology of degradative diseases.
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PMID:Metalloproteinase inhibitors: biological actions and therapeutic opportunities. 1223 82


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