Co-administration 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 (mm2), 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 micrograms rhIGF-I and 165 micrograms 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 micrograms were required for significant acceleration of the healing stimulated by 50 micrograms of rhIGF-I. In normal rabbits, co-administration of 10 micrograms rhIGF-I and 33 micrograms 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-I and rhIGFBP-1 for wound repair.
Tsuboi
R
R
Department of Dermatology, Juntendo University School of Medicine, Tokyo, Japan.
Shi
C M
CM
Sato
C
C
Cox
G N
GN
Ogawa
H
H
D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D013002:Somatomedins / Q000494:pharmacology; D013268:Stimulation, Chemical; D014945:Wound Healing / Q000187:drug effects*
D002352:Carrier Proteins; D018970:Insulin-Like Growth Factor Binding Protein 1; D011994:Recombinant Proteins; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I