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

Kevin B Hotary, Ikuo Yana, Farideh Sabeh, Xiao-Yan Li, Kenn Holmbeck, Henning Birkedal-Hansen, Edward D Allen, Nobuaki Hiraoka, Stephen J Weiss

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    186 Citationer (Scopus)

    Abstract

    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.

    OriginalsprogEngelsk
    TidsskriftThe Journal of Experimental Medicine
    Vol/bind195
    Udgave nummer3
    Sider (fra-til)295-308
    Antal sider14
    ISSN0022-1007
    StatusUdgivet - 4 feb. 2002

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