Induction of Keratinocyte Growth Factor Expression Is reduced and Delayed During Wound Healing in the Genetically Diabetic Mouse

Abstract

We have recently demonstrated induction of expression of several members of the fibroblast growth factor family during wound healing, particularly for keratinocyte growth factor, which was more than 150-fold induced within 24 h after injury. To assess whether wound-healing disorders are associated with a defect in fibroblast growth factor regulation, we have now investigated the expression of these mitogens as well as their receptors in normal and wounded skin of genetically diabetic db/db mice, which are characterized by their impaired wound healing. We demonstrate that induction of keratinocyte growth factor expression in these mice is significantly reduced and delayed compared to normal mice. Induction of acidic fibroblast growth factor (FGF) and basic FGF expression was earlier in diabetic mice than in normal mice, but by 3 d after injury expression of these mitogens had already returned to the basal levels. In contrast, elevated levels of acidic FGF and basic FGF transcripts were detected within the first 5 d in wounds from normal mice. Thus, FGFs seem to be expressed in a limited fashion in the wound tissue of db/db mice during the period when re-epithelialization and granulation tissue formation normally occur. These findings provide an explanation for the beneficial effect of exogenous FGF in the treatment of impaired wound healing in these animals and suggest that induction of KGF early in repair may be critical for the rapid re-epithelialization in normal wound healing.