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)

Many studies have highlighted the role played by matrix metalloproteinases MMP-2 and -9, by serine proteases uPA and plasmin in tumor cell invasion. This study investigates the impact of the MMP-inhibitor Batimastat and/or the serine protease inhibitor Aprotinin on the in vitro proteolytic activity and in vivo invasive behavior the of esophageal (OC1) and ovarian (OVCAR-3) carcinoma cells. In presence and absence of inhibitors, proteolytic activity of the tumor cells was determined by caseinolytic and collagenolytic in vitro assays and tumor cell invasion by intraperitoneal inoculation of the tumor cells into nude mice. In vitro, Aprotinin, tested alone or in combination with Batimastat, efficiently inhibited degradation of collagen IV and casein by the tumor cells. Batimastat alone had no effect on caseinolytic activities and only partially blocked collagen-type-IV-degradation by the tumor cells. In vivo, Aprotinin tested alone or in combination with Batimastat did not prevent tumor cell invasion. Treatment of tumor bearing mice with Batimastat significantly inhibited tumor growth but promoted tumor cell invasion into the liver. Our findings demonstrate that the inhibition pattern of cellular proteolytic activity achieved in vitro by a serine protease and an MMP inhibitor may lead to predictions that are not necessarily verified in vivo and may even have adverse effects.
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PMID:Combined treatment with serine protease inhibitor aprotinin and matrix metalloproteinase inhibitor Batimastat (BB-94) does not prevent invasion of human esophageal and ovarian carcinoma cells in vivo. 1062 17

The goal of articular cartilage tissue engineering is to provide cartilaginous constructs to replace abnormal cartilage. We have evaluated the chondroprogenitor clonal cell line RCJ3.1C5.18 (C5.18) as a model to guide the development of appropriate scaffolds for tissue engineering. Rapid degradation of fibrin hydrogels was observed after encapsulation of C5.18 cells. The enzymes responsible for this fibrin gel breakdown were characterized to control their activity and regulate gel stability. Western blotting, confirming zymography, revealed bands due to matrix metalloproteinases (MMP-2, MMP-3) that are secreted concomitantly with fibrin hydrogels breakdown. High plasmin activity was detected in conditioned media during hydrogel breakdown but not in the confluent cells before encapsulation. Reverse transcriptase polymerase chain reaction indicated the expression of MMP-2, -3, and -9 and plasminogen in the cells. MMP-9 was 100 times higher at day 1, whereas MMP-2 started to increase and reached its maximum level by day 7. Aprotinin, a known serine protease inhibitor, and galardin (GM6001), a potent MMP inhibitor, in combination or separately, prevented the breakdown of fibrin-C5.18 hydrogels, whereas only the combination of both promoted the accumulation of extracellular matrix. These findings suggest that plasmin and MMPs contribute independently to fibrin hydrogel breakdown, but that either enzyme can achieve extracellular matrix breakdown.
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PMID:Characterization and inhibition of fibrin hydrogel-degrading enzymes during development of tissue engineering scaffolds. 1751 6

Organogenesis involves a series of dynamic morphogenesis and remodeling processes. Since feathers exhibit complex forms, we have been using the feather as a model to analyze how molecular pathways and cellular events are used. While several major molecular pathways have been studied, the roles of matrix degrading proteases and inhibitors in feather morphogenesis are unknown. Here we addressed this knowledge gap by studying the temporal and spatial expression of proteases and inhibitors in developing feathers using mammalian antibodies that cross react with chicken proteins. We also investigated the effect of protease inhibitors on feather development employing an in vitro feather bud culture system. The results show that antibodies specific for mammalian MMP2 and TIMP2 stained positive in both feather epithelium and mesenchyme. The staining co-localized in structures of E10-E13 developing feathers. Interestingly, MMP2 and TIMP2 exhibited a complementary staining pattern in developing E15 and E20 feathers and in maturing feather filaments. Although they exhibited a slight delay in feather bud development, similar patterns of MMP2 and TIMP2 staining were observed in in vitro culture explants. The broad spectrum pharmacological inhibitors AG3340 and BB103 (MMP inhibitors) but not Aprotinin (a plasmin inhibitor) showed a reversible effect on epithelium invagination and feather bud elongation. TIMP2, a physiological inhibitor to MMPs, exhibited a similar effect. Markers of feather morphogenesis showed that MMP activity was required for both epithelium invagination and mesenchymal cell proliferation. Inhibition of MMP activity led to an overall delay in the expression of molecules that regulate either early feather bud growth and/or differentiation and thereby produced abnormal buds with incomplete follicle formation. This work demonstrates that MMPs and their inhibitors are not only important in injury repair, but also in development tissue remodeling as demonstrated here for the formation of feather follicles.
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PMID:From buds to follicles: matrix metalloproteinases in developmental tissue remodeling during feather morphogenesis. 2149 85