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© The Rockefeller University Press, 0021-9525/1997//67 $5.00
The Journal of Cell Biology, Volume 137, Number 1, , 1997 67-77

Article

Expression of Matrix Metalloproteinases during Rat Skin Wound Healing: Evidence that Membrane Type-1 Matrix Metalloproteinase Is a Stromal Activator of Pro-Gelatinase A



Akiko Okada, Catherine Tomasetto, Yves Lutz, Jean-Pierre Bellocq*, Marie-Christine Rio, and Paul Basset

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, BP 163, 67404 Illkirch Cedex, C.U. de Strasbourg, France; and * Service d'Anatomie Pathologique Générale, Hôpitaux Universitaires, Hôpital de Hautepierre, 67098 Strasbourg Cedex, France

Skin wound healing depends on cell migration and extracellular matrix remodeling. Both processes, which are necessary for reepithelization and restoration of the underlying connective tissue, are believed to involve the action of extracellular proteinases. We screened cDNA libraries and we found that six matrix metalloproteinase genes were highly expressed during rat skin wound healing. They were namely those of stromelysin 1, stromelysin 3, collagenase 3, gelatinase A (GelA), gelatinase B, and membrane type-1 matrix metalloproteinase (MT1-MMP). The expression kinetics of these MMP genes, the tissue distribution of their transcripts, the results of cotransfection experiments in COS-1 cells, and zymographic analyses performed using microdissected rat wound tissues support the possibility that during cutaneous wound healing pro-GelA and pro-gelatinase B are activated by MT1-MMP and stromelysin 1, respectively. Since MT1-MMP has been demonstrated to be a membrane-associated protein (Sato, H., T. Takino, Y. Okada, J. Cao, A. Shinagawa, E. Yamamoto, and M. Seiki. 1994. Nature (Lond.). 370: 61–65), our finding that GelA and MT1-MMP transcripts were expressed in stromal cells exhibiting a similar tissue distribution suggests that MT1-MMP activates pro-GelA at the stromal cell surface. This possibility is further supported by our observation that the processing of proGelA to its mature form correlated to the detection of MT1-MMP in cell membranes of rat fibroblasts expressing the MT1-MMP and GelA genes. These observations, together with the detection of high levels of the mature GelA form in the granulation tissue but not in the regenerating epidermis, suggest that MT1-MMP and GelA contribute to the restoration of connective tissue during rat skin wound healing.

Abbreviations used in this paper: Col1, interstitial collagenase; Col2, neutrophil collagenase; Col3, collagenase 3; ECM, extracellular matrix; GelA and GelB, gelatinase A and B; MMP, matrix metalloproteinase; MT1-MMP, MT2-MMP, MT3-MMP, and MT4-MMP, membrane-type-1, -2, -3, and -4 MMP; ST1, ST2, and ST3, stromelysin 1, 2, and 3; TIMP1, 2, and 3, tissue inhibitor of metalloproteinase type-1, -2, and -3.

Address all correspondence to Paul Basset, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, BP 163, 67404 Illkirch Cedex, France. Tel.: 33 3 88 65 34 25. Fax: 33 3 88 65 32 01. E-Mail: basset{at}igbmc.u-strasbg.fr

The current address of A. Okada is the Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo 108, Japan.


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