Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and -independent processes

Cross-linked fibrin is deposited in tissues surrounding wounds, inflammatory sites, or tumors and serves not only as a supporting substratum for trafficking cells, but also as a structural barrier to invasion. While the plasminogen activator-plasminogen axis provides cells with a powerful fibrinolyt...

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Bibliographic Details
Published in:The Journal of experimental medicine 2002-02, Vol.195 (3), p.295-308
Main Authors: Hotary, Kevin B, Yana, Ikuo, Sabeh, Farideh, Li, Xiao-Yan, Holmbeck, Kenn, Birkedal-Hansen, Henning, Allen, Edward D, Hiraoka, Nobuaki, Weiss, Stephen J
Format: Article
Language:English
Subjects:
Animals
Cell Line
CHO Cells
Cricetinae
Dogs
fibrin
Fibrin - metabolism
Fibrinolysis
Fibroblasts - cytology
Fibroblasts - metabolism
Matrix metalloproteinase
Matrix Metalloproteinase 14
Matrix Metalloproteinase 15
Matrix Metalloproteinase 16
Matrix Metalloproteinases - metabolism
Matrix Metalloproteinases, Membrane-Associated
Metalloendopeptidases - deficiency
Metalloendopeptidases - genetics
Metalloendopeptidases - metabolism
Mice
Mice, Knockout
Original
plasminogen
Transfection
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Summary:Cross-linked fibrin is deposited in tissues surrounding wounds, inflammatory sites, or tumors and serves not only as a supporting substratum for trafficking cells, but also as a structural barrier to invasion. While the plasminogen activator-plasminogen axis provides cells with a powerful fibrinolytic system, plasminogen-deleted animals use alternate proteolytic processes that allow fibrin invasion to proceed normally. Using fibroblasts recovered from wild-type or gene-deleted mice, invasion of three-dimensional fibrin gels proceeded in a matrix metalloproteinase (MMP)-dependent fashion. Consistent with earlier studies supporting a singular role for the membrane-anchored MMP, MT1-MMP, in fibrin-invasive events, fibroblasts from MT1-MMP-null mice displayed an early defect in invasion. However, MT1-MMP-deleted fibroblasts circumvented this early deficiency and exhibited compensatory fibrin-invasive activity. The MT1-MMP-independent process was sensitive to MMP inhibitors that target membrane-anchored MMPs, and further studies identified MT2-MMP and MT3-MMP, but not MT4-MMP, as alternate pro-invasive factors. Given the widespread distribution of MT1-, 2-, and 3-MMP in normal and neoplastic cells, these data identify a subset of membrane-anchored MMPs that operate in an autonomous fashion to drive fibrin-invasive activity.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20010815