Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we investigated the hypotheses that in human intervertebral disc (IVD) degeneration there is local production of the cytokine IL-1, and that this locally produced cytokine can induce the cellular and matrix changes of IVD degeneration. Immunohistochemistry was used to localize five members of the IL-1 family (IL-1alpha, IL-1beta, IL-1Ra (IL-1 receptor antagonist), IL-1RI (IL-1 receptor, type I), and ICE (IL-1beta-converting enzyme)) in non-degenerate and degenerate human IVDs. In addition, cells derived from non-degenerate and degenerate human IVDs were challenged with IL-1 agonists and the response was investigated using real-time PCR for a number of matrix-degrading enzymes, matrix proteins, and members of the IL-1 family. This study has shown that native disc cells from non-degenerate and degenerate discs produced the IL-1 agonists, antagonist, the active receptor, and IL-1beta-converting enzyme. In addition, immunopositivity for these proteins, with the exception of IL-1Ra, increased with severity of degeneration. We have also shown that IL-1 treatment of human IVD cells resulted in increased gene expression for the matrix-degrading enzymes (MMP 3 (matrix metalloproteinase 3), MMP 13 (matrix metalloproteinase 13), and ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs)) and a decrease in the gene expression for matrix genes (aggrecan, collagen II, collagen I, and SOX6). In conclusion we have shown that IL-1 is produced in the degenerate IVD. It is synthesized by native disc cells, and treatment of human disc cells with IL-1 induces an imbalance between catabolic and anabolic events, responses that represent the changes seen during disc degeneration. Therefore, inhibiting IL-1 could be an important therapeutic target for preventing and reversing disc degeneration.
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PMID:The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. 1598 75

Increased expression of metalloproteinases is a fundamental aspect of arthritispathology and its control is a major therapeutic objective. In cartilage cultured in the presence of the cytokines interleukin-1 and oncostatin M, chondrocytes produce enhanced levels of metalloproteinases of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and MMP (matrix metalloproteinase) families, resulting in the degradation of aggrecan and collagen. The histone deacetylase inhibitors trichostatin A and butyrate were shown to drastically reduce expression of these enzymes relatively selectively, with concomitant inhibition of breakdown of matrix components. This family of enzymes is therefore a promising target for therapeutic intervention.
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PMID:Histone deacetylases--a new target for suppression of cartilage degradation? 1589 37

Thrombospondin is a potent inhibitor of angiogenesis and might therefore be important in controlling tumour growth. TSP interacts with a number of proteases and receptors and in this way inhibits stimulation of angiogenesis. An earlier study showed that thrombospondin is expressed in benign prostatic hyperplasia (BPH) and high-grade prostatic intraepithelial neoplasia (PIN) but is absent in prostate cancer. The present study was therefore designed to evaluate the expression of thrombospondin 1 and 2 (TSP-1, TSP-2), TSP receptors CD36 and CD47, and matrix-metalloproteases 2 and 9 (MMP-, MMP-9) in a rat prostate cancer model. By using immunohistochemistry, Western blot, and real-time PCR the expression patterns of TSP-1, TSP-2, CD36, CD47, MMP-2, and MMP-9 were investigated in normal rat prostate tissue and five malignant Dunning sublines tissue. TSP-1 mRNA levels were decreased in all tumours compared with normal prostate. However, there was no difference in expression of TSP-2 and CD36 mRNA in these samples. MMP-2 was increased with malignancy, but no expression of MMP-9 was seen. The CD47 receptor did slightly increase with malignancy except for H3327. The results showed that thrombospondin is expressed in normal prostate but not in prostate tumours in a rat model. Simultaneously, MMP-2 expression increases with malignancy.
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PMID:Thrombospondins, metallo proteases and thrombospondin receptors messenger RNA and protein expression in different tumour sublines of the Dunning prostate cancer model. 1607 2

Members of the MMP (matrix metalloproteinase) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin type I motifs) families of enzymes are capable of cleaving a diverse array of cellular, extracellular and extracellular matrix substrates, including collagens and procollagens, proteoglycans, cytokines and cytokine ligands, chemokines, elastin and von Willebrand factor, thereby modulating tissue structure and function during both health and disease. Physiologically relevant roles attributable to various members of these metalloproteinase families have been discerned from functional studies correlating in vitro substrate processing events with catabolic cleavages occurring in vivo/in situ, and the consequences thereof. Mechanisms regulating the post-translational activities of MMPs and ADAMTSs can clearly also have an influential impact on cell metabolism and tissue structure/function, and a number of functional studies have addressed the contributions of ancillary (non-catalytic) domains and endogenous inhibitors in this regard. Further revelations and affirmations of proteinase function, in an in vivo context, have emanated with the characterization of genetically manipulated animals misexpressing specific MMPs or ADAMTSs (or their substrates). An increased understanding thereby attained for the physiological functions of MMPs and ADAMTSs, and the means by which their activities are controlled, may lead to the realization of rational therapeutic strategies to counteract pathologies associated with aberrant proteolysis of homeostatic tissue macromolecules.
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PMID:MMPs and ADAMTSs: functional studies. 1614 52

Protein microarrays are of increasing importance for high-throughput screening of fresh tissues. In our study, protein microarrays were generated by printing antibodies onto membranes to characterize protein profiles expressed by head and neck squamous cell carcinomas (HNSCCs). Cellular proteomes of 30 matched normal squamous epithelial cells and carcinoma specimens were analyzed after tissue microdissection using microarrays composed of 83 different antibodies. As controls, Western blot analysis and tissue microarrays (TMAs) containing 98 HNSCC specimens were used. Of the 83 proteins examined, 14 showed differential expression between HNSCCs and normal epithelium. The protein microarray approach revealed an upregulation of 8 proteins and a downregulation of 6 proteins. Bag-1, Cox-2, Hsp-70, Stat3, pescadillo, MMP-7 (matrilysin), IGF-2, and cyclin D1 were identified to be significantly upregulated, whereas suppressor of cytokine signaling 1, thrombospondin, TGF-beta1, Jun, Fos, and Fra-2 were downregulated. The differential expression of these proteins was confirmed using Western blot and TMA. Upon correlation of differentially regulated proteins with the clinicopathologic data of our patients, MMP-7 (matrilysin) was found to be associated with survival in univariate, but not multivariate, analysis. These data indicate that our protein arrays provide protein information in a systematic, reproducible, and also high-throughput fashion.
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PMID:Protein microarrays for the detection of biomarkers in head and neck squamous cell carcinomas. 1702 Jul 78

ADAMs (a disintegrin and metalloprotease) constitute a family of cell surface proteins containing disintegrin and metalloprotease domains which associate features of adhesion molecules and proteases. ADAMTSs (a disintegrin and metalloprotease with thrombospondin motifs) bear thrombospondin type I motifs in C-terminal extremity, and most of them are secreted proteins. Because genetic studies have shown that ADAM-33 gene polymorphisms are associated with asthma, we designed this study to assess mRNA expression profile of several ADAM and ADAMTS proteases in sputum from patients with asthma and to investigate the relationship between expression of these proteases and asthma-associated inflammation and airway obstruction. mRNA expression profile of selected ADAM and ADAMTS proteinases (ADAM-8, -9, -10, -12, -15, -17, and -33; ADAMTS-1, -2, -15, -16, -17, -18, and -19), their physiological inhibitors TIMP-1 and TIMP-3, and RECK, a membrane-anchored MMP activity regulator, was obtained by RT-PCR analysis performed on cells collected by sputum induction from 21 patients with mild to moderate asthma and 17 healthy individuals. mRNA levels of ADAM-8, ADAM-9, ADAM-12, TIMP-1, and TIMP-3 were significantly increased, whereas mRNA levels coding for ADAMTS-1, ADAMTS-15, and RECK were significantly decreased in patients with asthma compared with control patients. ADAM-8 expression was negatively correlated with the forced expiratory volume at the first second (FEV(1)) (r = -0.57, P < 0.01), whereas ADAMTS-1 and RECK expressions were positively correlated to FEV(1) (r = 0.45, P < 0.05, and r = 0.55, P = 0.01, respectively). We conclude that expression of ADAMs and ADAMTSs and their inhibitors is modulated in airways from patients with asthma and that these molecules may play a role in the pathogenesis of asthma.
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PMID:Expression of ADAMs and their inhibitors in sputum from patients with asthma. 1708 49

The five current members of the thrombospondin (TSP) family can be divided in two subgroups according to their molecular architecture. TSP-1 and -2 (subgroup A) are trimeric matricellular proteins that do not contribute directly to tissue integrity, but influence cell function by modulating cell-matrix interactions, whereas TSP-3, -4 and -5 (subgroup B) are pentameric proteins. TSP-1 and TSP-2 are markedly induced in healing wounds and may regulate cellular responses important for tissue repair. TSP-1 is a crucial activator of TGF-beta, whereas both TSP-1 and TSP-2 inhibit angiogenesis. This manuscript reviews our current knowledge on the expression and role of the TSPs in healing myocardial infarcts. In both canine and murine infarcts, TSP-1 shows a strikingly selective localization in the infarct border zone. In the absence of injury, TSP-1 -/- mice exhibit normal cardiac morphology and show no evidence of myocardial inflammation. Infarcted TSP-1 -/- mice have an enhanced and protracted inflammatory response with subsequent expansion of granulation tissue in the non-infarcted area, resulting in myofibroblast infiltration into the viable myocardium neighboring the infarct. Infarcted TSP-1 -/- animals have enhanced left ventricular remodeling compared with their wildtype littermates. We suggest that TSP-1 is a critical component of the protective mechanisms induced in the infarct border zone in order to limit expansion of fibrosis into the non-infarcted myocardium. Localized TSP-1 expression may suppress expansion of the inflammatory process by activating TGF-beta or by inhibiting local angiogenesis. In addition, TSP-1-mediated inhibition of MMP activity may decrease adverse remodeling. TSP-2, on the other hand, appears to be a crucial regulator of the integrity of the cardiac matrix that is necessary for the myocardium to cope with increased loading. The expression and potential role of the pentameric TSPs in the infarcted heart remain unknown. Understanding the specific mechanisms responsible for the protective effects of TSP-1 and TSP-2 in healing infarcts may lead to novel therapeutic interventions aiming at attenuating adverse left ventricular remodeling.
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PMID:The role of the thrombospondins in healing myocardial infarcts. 1726 45

Degeneration of the intervertebral disc has been implicated in chronic low back pain. Type II collagen and proteoglycan (predominantly aggrecan) content is crucial to proper disc function, particularly in the nucleus pulposus. In degeneration, synthesis of matrix molecules changes, leading to an increase in the synthesis of collagens type I and III and a decreased production of aggrecan. Linked to this is an increased expression of matrix-degrading molecules including MMPs (matrix metalloproteinases) and the aggrecanases, ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) 1, 4, 5, 9 and 15, all of which are produced by native disc cells. Importantly, we have found that there is a net increase in these molecules, over their natural inhibitors [TIMP-1 (tissue inhibitor of metalloproteinases-1), 2 and 3], suggesting a deregulation of the normal homoeostatic mechanism. Growth factors and cytokines [particularly TNFalpha (tumour necrosis factor alpha) and IL-1 (interleukin 1)] have been implicated in the regulation of this catabolic process. Our work has shown that in degenerate discs there is an increase in IL-1, but no corresponding increase in the inhibitor IL-1 receptor antagonist. Furthermore, treatment of human disc cells with IL-1 leads to a decrease in matrix gene expression and increased MMP and ADAMTS expression. Inhibition of IL-1 would therefore be an important therapeutic target for preventing/reversing disc degeneration.
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PMID:Matrix synthesis and degradation in human intervertebral disc degeneration. 1763 13

The Maillard reaction and its end products, AGE-s (Advanced Glycation End products) are rightly considered as one of the important mechanisms of post-translational tissue modifications with aging. We studied the effect of two AGE-products prepared by the glycation of lysozyme and of BSA, on the expression profile of a large number of genes potentially involved in the above mentioned effects of AGE-s. The two AGE-products were added to human skin fibroblasts and gene expression profiles investigated using microarrays. Among the large number of genes monitored the expression of 16 genes was modified by each AGE-preparations, half of them only by both of them. Out of these 16 genes, 12 were more strongly affected, again not all the same for both preparations. Both of them upregulated MMP and serpin-expression and downregulated some of the collagen-chain coding genes, as well as the cadherin- and fibronectin genes. The BSA-AGE preparation downregulated 10 of the 12 genes strongly affected, only the serpin-1 and MMP-9 genes were upregulated. The lysozyme-AGE preparation upregulated selectively the genes coding for acid phosphatase (ACP), integrin chain alpha5 (ITGA5) and thrombospondin (THBS) which were unaffected by the BSA-AGE preparation. It was shown previously that the lysozyme-AGE strongly increased the rate of proliferation and also cell death, much more than the BSA-AGE preparation. These differences between these two AGE-preparations tested suggest the possibility of different receptor-mediated transmission pathways activated by these two preparations. Most of the gene-expression modifications are in agreement with biological effects of Maillard products, especially interference with normal tissue structure and increased tissue destruction.
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PMID:Effect of advanced glycation endproducts on gene expression profiles of human dermal fibroblasts. 1829 8

Previous studies reported that modification in the expression of the matricellular multidomain glycoprotein thrombospondin-1 (TSP-1) could play a critical role in the control of tumor progression and metastasis development. The function of this multimodular protein in cancers appears highly dependent on the cellular context and thus remains to date very difficult to accurately characterize. Controversial results indeed exist reporting either pro- or anti-invasive properties of TSP-1. Since it appeared that TSP-1 could be of prognostic value for certain specific types of cancers, we examined in this study the prospective function of TSP-1 in the control of human follicular thyroid carcinoma (FTC) cell invasiveness. First, we established that the aggressive behavior of human thyroid malignant cells is closely correlated to the TSP-1 amount. We demonstrated that exogenously added TSP-1 stimulates by two-fold the capacity of FTC cells to invade Matrigel-coated wells. The use of specific anti-TSP-1 blocking antibodies led to a drastic inhibition of the basal FTC cell invasion. Zymography experiments revealed that the uPA-dependent proteolytic activity is directly controlled by TSP-1, MMPs activity is not. The TSP-1-mediated stimulation of uPA appears to occur at post-transcriptional level. Finally, we established that the TSP-1-stimulated FTC cell invasion is wholly abolished under anti-uPA blocking antibodies or aprotinin treatments whereas MMP inhibitors have no effect. All together, we evidenced in the present study that TSP-1 promotes human follicular thyroid carcinoma cell invasion mainly through up-regulation of the urokinase-dependent activity.
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PMID:Thrombospondin-1 enhances human thyroid carcinoma cell invasion through urokinase activity. 1832 63


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