Expression of glycosaminoglycans and small proteoglycans in wounds: Modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+

Glycyl-histidyl-lysine-Cu2+ is a tripeptide-copper complex previously shown to be an activator of wound healing. We have investigated the effects of g lycyl-histidyl-lysine-Cu2+ on the synthesis of glycosaminoglycans and small proteoglycans in a model of rat experimental wounds and in rat dermal fibr oblast cultures. Repeated injections of glycyl-histidyl-lysine-Cu2+ (2 mg p er 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 (assesse d, respectively, by hydroxyproline and uronic acid contents of the chamber) . Electrophoretic analysis of wound tissue glycosaminoglycans showed an acc umulation of chondroitin sulfate and dermatan sulfate in control wound cham bers, whereas the proportion of hyaluronic acid decreased with time. The ac cumulation of chondroitin sulfate and dermatan sulfate was enhanced by glyc yl-histidyl-lysine-Cu2+ treatment. The expression of two small proteoglycan s of the dermis, decorin and biglycan, was analyzed by northern blot. The b iglycan mRNA steady-state level in the chamber was maximal at day 12, where as the decorin mRNA increased progressively until the end of the experiment (day 22). Glycyl-histidyl-lysine-Cu2+ treatment increased the mRNA level o f decorin and decreased those of biglycan. In dermal fibroblast cultures, t he stimulation of decorin expression by glycyl-histidyl-lysine-Cu2+ was als o found. In contrast, biglycan expression was not modified. These results s how that the expression of different proteoglycans in wound tissue are regu lated in a different manner during wound healing. The glycyl-histidyl-lysin e-Cu2+ complex is able to modulate the expression of the extracellular matr ix macromolecules differently during the wound repair process.