Recently we demonstrated that urokinase plasminogen activator (uPA) expression was selectively and consistently induced in hyperproliferative murine epidermis. These unexpected observations suggested that uPA may be a positive regulator of epidermal proliferation. To test this hypothesis, we quantified the proliferative response of newborn mice that bear a targeted deletion of the uPA gene. Since newborn mouse epidermis is normally hyperproliferative, we predicted that mice lacking the uPA gene would exhibit an abnormally low proliferative rate. As predicted, the epidermal proliferative index during days 1-3 of life was decreased by 35-40% in uPA-'- mice compared with the wild type or with tissue PA(tPA)-'- mice. However, this inhibition of proliferation was transient, as the proliferative index of the uPA"'" mice became indistinguishable from that of normal mice by day 4 of life. Epidermal Proliferative Index * uPA-/- wild type tPA-/- day of life 1 7.9 ± 1.3 (15) 12.0 ± 1.8 (12) 13.7 ± 3.1 (8) 3 11.3 ± 2.1 (10) 18.4 ± 4.7 (14) 18.6 ± 3.2 (7) 4 18.1 ± 3.4 (9) 16.9 ± 4.9 (11) 18.5 ± 3.2 (6) 5 15.8 ± 1.8 (8) 18.1 ± 3.1 (5) 23.5 ± 2.9 (4) Average percentage ± SD of basal cells incorporating BrdU after a 90 min pulse in vivo. Numbers in parentheses indicate the number of mice tested. A possible explanation for the rapid attainment of a normal proliferative rate by neonatal uPA-'- epidermis may be the following: normal murine epidermis contains not only uPA but also tPA activity, which may compensate for uPA in uPA-'- mice. Zymographic analysis suggested that this is indeed the case. In 14 out of 18 age-matched samples, uPA" epidermal extracts contained greater levels of tPA activity than wild type extracts. These data suggest that: (i) uPA is a positive regulator of epidermal proliferation and (ii) epidermal keratinocytes may attempt to compensate for the lack of uPA by enhancement of tPA activity.
|Original language||English (US)|
|Number of pages||1|
|Journal||Fibrinolysis and Proteolysis|
|Issue number||SUPPL. 3|
|State||Published - Dec 1 1997|
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