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)

Human macrophages are believed to damage host tissues in chronic inflammatory disease states, but these cells have been reported to express only modest degradative activity in vitro. However, while examining the ability of human monocytes to degrade the extracellular matrix component elastin, we identified culture conditions under which the cells matured into a macrophage population that displayed a degradative phenotype hundreds of times more destructive than that previously ascribed to any other cell population. The monocyte-derived macrophages synthesized elastinolytic matrix metalloproteinases (i.e., gelatinase B and matrilysin) as well as cysteine proteinases (i.e., cathepsins B, L, and S), but only the cathepsins were detected in the extracellular milieu as fully processed, mature enzymes by either vital fluorescence or active-site labeling. Consistent with these observations, macrophage-mediated elastinolytic activity was not affected by matrix metalloproteinase inhibitors but could be almost completely abrogated by inhibiting cathepsins L and S. These data demonstrate that human macrophages mobilize cysteine proteinases to arm themselves with a powerful effector mechanism that can participate in the pathophysiologic remodeling of the extracellular matrix.
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PMID:Pericellular mobilization of the tissue-destructive cysteine proteinases, cathepsins B, L, and S, by human monocyte-derived macrophages. 773 94

We have studied the degradation of type X collagen by metalloproteinases, cathepsin B, and osteoclast-derived lysates. We had previously shown (Welgus, H. G., C. J. Fliszar, J. L. Seltzer, T. M. Schmid, and J. J. Jeffrey. 1990. J. Biol. Chem. 265:13521-13527) that interstitial collagenase rapidly attacks the native 59-kD type X molecule at two sites, rendering a final product of 32 kD. This 32-kD fragment, however, has a Tm of 43 degrees C due to a very high amino acid content, and thus remains helical at physiologic core temperature. We now report that the 32-kD product resists any further attack by several matrix metalloproteinases including interstitial collagenase, 92-kD gelatinase, and matrilysin. However, this collagenase-generated fragment can be readily degraded to completion by cathepsin B at 37 degrees C and pH 4.4. Interestingly, even under acidic conditions, cathepsin B cannot effectively attack the whole 59-kD type X molecule at 37 degrees C, but only the 32-kD collagenase-generated fragment. Most importantly, the 32-kD fragment was also degraded at acid pH by cell lysates isolated from murine osteoclasts. Degradation of the 32-kD type X collagen fragment by osteoclast lysates exhibited the following properties: (a) cleavage occurred only at acidic pH (4.4) and not at neutral pH; (b) the cysteine proteinase inhibitors E64 and leupeptin completely blocked degradation; and (c) specific antibody to cathepsin B was able to inhibit much of the lysate-derived activity. Based upon these data, we postulate that during in vivo endochondral bone formation type X collagen is first degraded at neutral pH by interstitial collagenase secreted by resorbing cartilage-derived cells. The resulting 32-kD fragment is stable at core temperature and further degradation requires osteoclast-derived cathepsin B supplied by invading bone.
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PMID:Complete degradation of type X collagen requires the combined action of interstitial collagenase and osteoclast-derived cathepsin-B. 773 76

Carrier-mediated prostaglandin transport has been postulated to occur in many tissues. On the basis of sequence homology, the protein of unknown function encoded by the rat matrin F/G complementary DNA was predicted to be an organic anion transporter. Expression of the matrin F/G complementary DNA in HeLa cells or Xenopus oocytes conferred the property of specific transport of prostaglandins. The tissue distribution of matrin F/G messenger RNA and the sensitivity of matrin F/G-induced prostaglandin transport to inhibitors were similar to those of endogenous prostaglandin transport. The protein encoded by the matrin F/G complementary DNA is thus preferably called PGT because it is likely to function as a prostaglandin transporter.
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PMID:Identification and characterization of a prostaglandin transporter. 775 69

Matrix metalloproteases are a family of enzymes that play critical roles in the physiological and pathological degradation of the extracellular matrix. These enzymes may be important therapeutic targets for the treatment of various diseases where tissue degradation is part of the pathology, such as cancer and arthritis. Matrilysin is the smallest member of this family of enzymes, all of which require zinc for catalytic activity. The first X-ray crystal structures of human matrilysin are presented. Inhibitors of metalloproteases are often characterized by the chemical group that interacts with the active site zinc of the protein. The structures of matrilysin complexed with hydroxamate (maximum resolution 1.9 A), carboxylate (maximum resolution 2.4 A), and sulfodiimine (maximum resolution 2.3 A) inhibitors are presented here and provide detailed information about how each functional group interacts with the catalytic zinc. Only the zinc-coordination group is variable in this series of inhibitors. Examination of these inhibitor-matrilysin complexes emphasizes the dominant role the zinc-coordinating group plays in determining the relative potencies of the inhibitors. The structures of these matrilysin-inhibitor complexes also provide a basis for comparing the catalytic mechanism of MMPs and other metalloproteins.
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PMID:Matrilysin-inhibitor complexes: common themes among metalloproteases. 775 91

Matrilysin is a recently described metalloproteinase with strong catalytic activity against a variety of extracellular matrix substrates including proteoglycans, elastin, laminin, fibronectin, gelatin, and entactin. Production of this metalloproteinase appears to be limited only to a few normal human cell types including glandular epithelium, mononuclear phagocytes, and renal mesangial cells. Furthermore, matrilysin expression in vivo has been demonstrated only in glandular epithelium, especially the endometrium. In the process of examining various cutaneous and lung inflammatory disorders for matrilysin expression by immunohistochemistry and in situ hybridization, we occasionally found monocytes within blood vessels and newly extravasated tissue-associated macrophages that exhibited matrilysin production. In specimens characterized by severe inflammation and, in particular, cystic fibrosis, this feature was commonly observed. We therefore studied the production of matrilysin by monocyte-derived macrophages in vitro in response to various physiologic signals such as endotoxin, phagocytosable material, cytokines, and hormones. We found that matrilysin expression was stimulated by LPS and opsonized zymosan. Up-regulation of matrilysin by LPS was PGE2-dependent, because indomethacin blocked production, an effect at least partially reversed by the addition of exogenous prostaglandin. LPS stimulated matrilysin production pretranslationally and, furthermore, when cultured cells were subjected to in situ hybridization after LPS exposure, considerable variability in matrilysin mRNA expression was observed on an individual cell basis, with some cells having strong signal and others being completely negative. We also found that matrilysin biosynthesis was inhibited by the lymphokines IL-4, IL-10, and IFN-gamma. Other cytokines such as IL-1, TNF-alpha, and IL-6 failed to modulate the production of matrilysin. Finally, matrilysin biosynthesis was suppressed by glucocorticoids and retinoids. Our studies indicate that matrilysin is produced in vivo by mononuclear phagocytes and is a highly regulated metalloproteinase whose production can be modified by a variety of physiologic and pharmacologic signals.
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PMID:Matrilysin expression by human mononuclear phagocytes and its regulation by cytokines and hormones. 775 83

Tumor necrosis factor-alpha (TNF-alpha) is released from a cell membrane-anchored precursor by proteolytic cleavage. We have shown that broad spectrum synthetic inhibitors of matrix metalloproteinases (MMPs) prevent the processing of the TNF precursor but do not inhibit the release of other cytokines. Purified MMPs, stromelysin, matrilysin, collagenase, and the gelatinases can all cleave a recombinant pro-TNF substrate to yield mature TNF. MMP inhibitors prevent the rise in blood levels of TNF after endotoxin administration in rats and are effective in animal models of inflammatory disease such as adjuvant arthritis. Drugs that inhibit MMP action and TNF release show great promise for the treatment of autoimmune inflammatory diseases.
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PMID:Matrix metalloproteinases and processing of pro-TNF-alpha. 775 57

Immunohistochemical studies of prostate carcinoma reveal that most primary carcinomas, including high-grade tumors, are surrounded by a basal lamina composed of laminin, type IV collagen, and entactin. In addition to the expected laminin subchains A, B1, B2, subchains M and S are also found. Tenascin, found around normal glands, is seen in 60% of carcinomas. The basal cells of the normal gland express several integrin alpha units including alpha 2,3,4,5,6, and v. Both beta 1 and beta 4 subunits are observed. These integrin units are polarized at the base of the cells where they codistribute with the surrounding extracellular matrix. The integrin alpha 6 beta 4 is associated with hemidesmosomal-like structures, as detected by transmission electron microscopy (TEM). In carcinoma, the beta 4 is not observed and the alpha 6 and beta 1 subunits are variably expressed. The integrin expression in carcinoma is diffuse in the cytoplasmic membrane and not restricted to the basal aspects of the cell. In addition, type VII collagen and the BP 180 protein which are associated with hemidesmosomes are lost, although the BP 230, plectin, and HD1 proteins are variably expressed. Using immunohistochemistry and northern analysis we observed three metalloproteinases in prostate carcinoma--matrilysin, gelatinase A, and gelatinase B. Western blotting and zymogram analysis reveal that of these three, only matrilysin appears to be present in its active form. Recent in situ hybridization studies reveal focal expression of the matrilysin mRNA in 25/33 primary carcinomas. Matrilysin also appears to be highly expressed in prostatic ducts and atrophic glands. Expression of the three metalloproteinases is also seen in prostatic intraepithelial neoplasia lesions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adhesion molecules, extracellular matrix, and proteases in prostate carcinoma. 782 96

Type XIV collagen is a newly described member of the fibril-associated collagens with interrupted triple helices (FACITs). Expression of this collagen has been localized to various embryonic tissues, suggesting that it has a functional role in development. All FACITs thus far described (types IX, XII, XIV, and XVI) contain a highly homologous carboxyl-terminal triple helical domain designated COL1. We have studied the capacity of various matrix metalloproteinases (interstitial collagenase, stromelysin, matrilysin, and 92-kDa gelatinase) to degrade the COL1 domain of collagen XIV. We found that only 92-kDa gelatinase cleaves COL1. Furthermore, digestion of whole native collagen XIV by the 92-kDa gelatinase indicates that this enzyme specifically attacks the carboxyl-terminal triple helix-containing region of the molecule. COL1 is cleaved by 92-kDa gelatinase at 30 degrees C, a full 5-6 degrees C below the melting temperature (Tm) of this domain; native collagen XIV is also degraded at 30 degrees C. In comparison to interstitial collagenase degradation of its physiologic native type I collagen substrate, the 92-kDa enzyme cleaved COL1 (XIV) with comparable catalytic efficacy. Interestingly, following thermal denaturation of the COL1 fragment, its susceptibility to 92-kDa gelatinase increases, but only to a degree that leaves it several orders of magnitude less sensitive to degradation than denatured collagens I and III. These data indicate that native COL1 and collagen XIV are readily and specifically cleaved by 92-kDa gelatinase. They also suggest a role for 92-kDa gelatinase activity in the structural tissue remodeling of the developing embryo.
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PMID:Degradation of the COL1 domain of type XIV collagen by 92-kDa gelatinase. 783 60

Interest in orthotopic models has been generated by recent reports of increased invasive and metastatic potential demonstrated by tumor cell lines following injection into their tissue of origin rather than subcutaneously. We have previously demonstrated that transfection of the tumorigenic human prostate cell line, Du-145, with the metalloproteinase matrilysin increased its ability to invade the diaphragm following an intraperitoneal injection. In this study we compare the invasive and metastatic behavior of transfected Du-145 cell lines injected into the dorsal lateral lobe of the prostate to that observed when they are injected intraperitoneally. Immunohistochemistry was used to examine 37 orthotopically injected severe combined immunodeficient mice for local invasion and metastatic lesions. In addition, the effect of injection site on the level of expression of four genes thought to influence the invasiveness of tumor cells (matrilysin, stromelysin, TIMP-1, and TIMP-2), was determined by northern analysis of orthotopic and subcutaneous tumor tissue. The results demonstrate that the level of mRNA expression of the genes examined was similar at the two sites of injection and that the invasive properties of Du-145 cells following orthotopic implantation were comparable to that observed on the diaphragm following intraperitoneal injection. The advantages of the diaphragm invasion model are: less procedure-related mortality, ease of cell delivery, and provision of an easily orientated structure in which the earliest penetration of a basal lamina can be observed.
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PMID:Prostate tumor cell invasion: a comparison of orthotopic and ectopic models. 786 Feb 25

The discovery of useful peptide substrates for proteases that recognize many amino acids in their active sites is often a slow process due to the lack of initial substrate data and the expense of analyzing large numbers of peptide substrates. To overcome these obstacles, we have made use of bacteriophage peptide display libraries. We prepared a random hexamer library in the fd-derived vector fAFF-1 and included a "tether" sequence that could be recognized by monoclonal antibodies. We chose the matrix metalloproteinases stromelysin and matrilysin as the targets for our studies, as they are known to require at least 6 amino acids in a peptide substrate for cleavage. The phage library was treated in solution with protease and cleaved phage separated from uncleaved phage using a mixture of tether-binding monoclonal antibodies and Protein A-bearing cells followed by precipitation. Clones were screened by the use of a rapid screening assay that identified phage encoding peptide sequences susceptible to cleavage by the enzymes. The nucleotide sequence of the random hexamer region of 43 such clones was determined for stromelysin and 23 for matrilysin. Synthetic peptides were prepared whose sequences were based on some of the positive clones, as well as consensus sequences built from the positive clones. Many of the peptides have kcat/KM values as good or better than those of previously reported substrates, and in fact, we were able to produce stromelysin and matrilysin substrates that are both the most active and smallest reported to date. In addition, the phage data predicted selectivity in the P2 and P'1 positions of the two enzymes that were supported by the kinetic analysis of the peptides. This work demonstrates that the phage selection techniques enable the rapid identification of highly active and selective protease substrates without making any a priori assumptions about the specificity or the "physiological substrate" of the protease under study.
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PMID:Rapid identification of highly active and selective substrates for stromelysin and matrilysin using bacteriophage peptide display libraries. 789 77


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