The Journal of Experimental Medicine
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Published 28 January 2002. doi:10.1084/jem.20010815
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© Rockefeller University Press, 0022-1007/2002/2/295/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 3, February 4, 2002 295-308

Original Article

Matrix Metalloproteinases (MMPs) Regulate Fibrin-invasive Activity via MT1-MMP–dependent and –independent Processes

Kevin B. Hotary1, Ikuo Yana1, Farideh Sabeh1, Xiao-Yan Li1, Kenn Holmbeck2, Henning Birkedal-Hansen2, Edward D. Allen1, Nobuaki Hiraoka1 and Stephen J. Weiss1

1 University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
2 National Institutes of Health/National Institute of Dental and Craniofacial Research, Bethesda, MD 20892

Address correspondence to Stephen J. Weiss, 5220 MSRB III, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0640. Phone: 734-764-0030; Fax: 734-764-0101; E-mail: SJWEISS{at}umich.edu

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.

Key Words: matrix metalloproteinases • MT-MMP • fibrin • proteolysis • invasion


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