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.
| Original language | English |
|---|---|
| Journal | The Journal of Experimental Medicine |
| Volume | 195 |
| Issue number | 3 |
| Pages (from-to) | 295-308 |
| Number of pages | 14 |
| ISSN | 0022-1007 |
| Publication status | Published - 4 Feb 2002 |
Keywords
- Animals
- CHO Cells
- Cell Line
- Cricetinae
- Dogs
- Fibrin/metabolism
- Fibrinolysis
- Fibroblasts/cytology
- Matrix Metalloproteinase 14
- Matrix Metalloproteinase 15
- Matrix Metalloproteinase 16
- Matrix Metalloproteinases/metabolism
- Matrix Metalloproteinases, Membrane-Associated
- Metalloendopeptidases/deficiency
- Mice
- Mice, Knockout
- Transfection