Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+).

Glycyl-histidyl-lysine-Cu(2+) is a tripeptide-copper complex previously shown to be an activator of wound healing. We have investigated the effects of glycyl-histidyl-lysine-Cu(2+) on the synthesis of glycosaminoglycans and small proteoglycans in a model of rat experimental wounds and in rat dermal fibroblast cultures. Repeated injections of glycyl-histidyl-lysine-Cu(2+) (2 mg per injection) stimulated the wound tissue production, as appreciated by dry weight and total protein measurements. This stimulation was accompanied by an increased production of type I collagen and glycosaminoglycans (assessed, respectively, by hydroxyproline and uronic acid contents of the chamber). Electrophoretic analysis of wound tissue glycosaminoglycans showed an accumulation of chondroitin sulfate and dermatan sulfate in control wound chambers, whereas the proportion of hyaluronic acid decreased with time. The accumulation of chondroitin sulfate and dermatan sulfate was enhanced by glycyl-histidyl-lysine-Cu(2+) treatment. The expression of two small proteoglycans of the dermis, decorin and biglycan, was analyzed by northern blot. The biglycan mRNA steady-state level in the chamber was maximal at day 12, whereas the decorin mRNA increased progressively until the end of the experiment (day 22). Glycyl-histidyl-lysine-Cu(2+) treatment increased the mRNA level of decorin and decreased those of biglycan. In dermal fibroblast cultures, the stimulation of decorin expression by glycyl-histidyl-lysine-Cu(2+) was also found. In contrast, biglycan expression was not modified. These results show that the expression of different proteoglycans in wound tissue are regulated in a different manner during wound healing. The glycyl-histidyl-lysine-Cu(2+) complex is able to modulate the expression of the extracellular matrix macromolecules differently during the wound repair process.