COADMINISTRATION OF INSULIN-LIKE GROWTH-FACTOR (IGF)-I AND IGF-BINDING PROTEIN-1 STIMULATES WOUND-HEALING IN ANIMAL-MODELS

The stimulatory effect of recombinant human insulin-like growth factor-I (rhIGF-I) and recombinant human insulin-like growth-factor-binding protein-1 (rhIGFBP-1) on wound healing was assessed using diabetic db/db mice and normal rabbits. Full-thickness wounds of 6 mm diameter were prepared on the backs of diabetic C57BL/KsJ db/db mice and on the inner sides of normal rabbit ears, Various concentrations of rhIGF-I and/or rhIGFBP-1 were applied locally to the open wounds of db/db mice once daily for 5 d and to the covered wounds of normal rabbits once after wounding, Sections of the wounds were evaluated histologically on the seventh or eighth day by measuring re-epithelialization (%), area of granulation tissue (mm(2)), and capillary numbers, Wound repair was accelerated by each of the treatments in descending order of rhIGF-I plus rhIGFBP-1, rhIGF-I, rhIGFBP-1, and vehicle alone, In db/db mice, the combination of 50 mu g rhIGF-I and 165 mu g rhIGFBP-1 (equimolar ratio) significantly stimulated granulation tissue formation (p < 0.01) and capillary numbers (p < 0.05), Doses of rhIGFBP-1 greater than 16.5 mu g were required for significant acceleration of the healing stimulated by 50 mu g of rhIGF-I. In normal rabbits, co-administration of 10 mu g rhIGF-I and 33 mu g rhIGFBP-1 (equimolar ratio) significantly stimulated all three wound-healing parameters (p < 0.01), with such stimulation being much greater than that induced by rhIGF-I alone, Interestingly, rhIGFBP-1 alone showed a mild stimulatory activity on wound healing in both models despite its lack of mitogenic activity in vitro, These results demonstrate that rhIGFBP-1 enhances the stimulatory activity of rhIGF-I on wound healing and suggest the clinical utility of the co-administration of rhIGF-1 and rhIGFBP-1 for wound repair.