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Vol. 15, Issue 12, 5242-5254, December 2004

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Activities of the Matrix Metalloproteinase Stromelysin-2 (MMP-10) in Matrix Degradation and Keratinocyte Organization in Wounded Skin

Monika Krampert ^*, Wilhelm Bloch , Takako Sasaki , Philippe Bugnon ^*, Thomas Rülicke , Eckhard Wolf ^||, Monique Aumailley ^¶, William C. Parks ^#, and Sabine Werner ^* @

^* Department of Biology, Institute of Cell Biology, Eidgenössishe Technische Hochschule Zurich, 8093 Zurich, Switzerland; Department of Molecular and Cellular Sport Medicine, German Sports University, D-50927 Cologne, Germany; Department of Molecular Medicine, Max-Planck Institute of Biochemistry, D-82152 Martinsried, Germany; Institute for Laboratory Animal Sciences, University of Zurich, CH-8091 Zurich, Switzerland; ^|| Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians University, D-81377 Munich, Germany; ^¶ Institute of Biochemistry II and Center for Molecular Medicine, University of Cologne, D-50931 Cologne, Germany; and ^# Department of Medicine, University of Washington, Seattle, WA 98104

Submitted February 9, 2004; Revised September 3, 2004; Accepted September 8, 2004
Monitoring Editor: Jean Schwarzbauer

The matrix metalloproteinase stromelysin-2 is expressed in keratinocytes of the epithelial tongue of skin wounds, suggesting a role in keratinocyte migration. Here, we show that stromelysin-2 enhances migration of cultured keratinocytes. To gain insight into the in vivo activities of stromelysin-2 in epithelial repair, we generated transgenic mice expressing a constitutively active stromelysin-2 mutant in keratinocytes. These animals had no alterations in skin architecture, and the healing rate of skin wounds was normal. Histologically, however, we found abnormalities in the organization of the wound epithelium. Keratinocytes at the migrating epidermal tip were scattered in most sections of mice with high expression level, and there was a reduced deposition of new matrix. In particular, the staining pattern of laminin-5 at the wound site was altered. This may be due to proteolytic processing of laminin-5 by stromelysin-2, because degradation of laminin-5 by this enzyme was observed in vitro. The inappropriate matrix contact of keratinocytes was accompanied by aberrant localization of 1-integrins and phosphorylated focal adhesion kinase, as well as by increased apoptosis of wound keratinocytes. These results suggest that a tightly regulated expression level of stromelysin-2 is required for limited matrix degradation at the wound site, thereby controlling keratinocyte migration.

^@ Corresponding author. E-mail address: sabine.werner{at}cell.biol.ethz.ch.

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