Functional overlap between two classes of matrix-degrading proteases in wound healing

Retarded mound healing was found in mice deficient in the serine protease p recursor plasminogen, as well as in wild-type mice treated with the metallo protease inhibitor galardin, but in both cases wound closure was ultimately completed in all mice within 60 days. The expression of several matrix met alloproteases in keratinocytes migrating to cover the wound was strongly en hanced by galardin treatment, However, when plasminogen-deficient mice were treated with galardin, healing was completely arrested and mound closure w as not seen during an observation period of 100 days, demonstrating that pr otease activity is essential for skin wound healing. The requirement for bo th plasminogen deficiency and metalloprotease inhibition for complete inhib ition of the healing process indicates that there is a functional overlap b etween the two classes of matrix-degrading proteases, probably in the disse ction of the fibrin-rich provisional matrix by migrating keratinocytes, Eac h class alone is capable of maintaining sufficient keratinocyte migration t o regenerate the epidermal surface, although this function mould normally b e performed by both classes acting in parallel. Since there are strong simi larities between the proteolytic mechanisms in wound healing and cancer inv asion, these results predict that complete arrest of this latter process in therapeutic settings will require the use of inhibitors of both classes of proteases.