title: Interaction between the insulin-like growth factor family and the integrin receptor family in tissue repair processes. Evidence in a rabbit ear dermal ulcer model.
abstract: We have determined previously that IGF-I is dependent on the presence of IGF binding protein-1 (IGFBP-1) to act as a wound healing agent. We sought to determine the mechanism whereby IGFBP-1 is able to enhance IGF-I bioactivity. As IGFBP-1 binds both the alpha5beta1 integrin as well as IGF-I in vitro, we asked which of the following interactions were important: (a) the ability of IGFBP-1 to interact with an integrin receptor, and/or (b) the binding of IGF-I by IGFBP-1. We used an IGF-1 analogue (des(1-3)IGF-I) with a > 100-fold reduction in affinity for IGFBP-1 as well as an IGFBP-1 mutant (WGD-IGFBP-1) which does not associate with the alpha5beta1 integrin to selectively abrogate each of these interactions. We also tested the ability of IGFBP-2, a related binding protein which has an arginine-glycine-aspartate sequence but does not associate with integrin family members, to enhance IGF-I bioactivity. Full-thickness dermal wounds were created on rabbit ears; various combinations of native IGF-I, native IGFBP-1, native IGFBP-2, and their respective analogues/mutants were applied to each wound. Wounds were harvested 7 d later for analysis. Only native IGF-I in combination with native IGFBP-1 was effective as a wound healing agent, enhancing reepithelialization and granulation tissue deposition by 64+/-5 and 83+/-12% over controls (P = 0.008 and 0.016, respectively). The same doses of IGF-I/WGD-IGFBP-1, des(1-3)IGF-I/IGFBP-1, and IGF-I/IGFBP-2 were ineffective. We propose that IGF-I physically interacts with IGFBP-1 and that IGFBP-1 also binds to an integrin receptor, most likely the alpha5beta1 integrin. This interaction is unique to IGFBP-1 as the closely related IGFBP-2 had no effect, a finding consistent with its inability to bind to integrin receptors. Our results suggest that activation of both the IGF-I receptor and the alpha5beta1 integrin is required for IGF-I to stimulate wound healing.
authors.affiliation: Division of Plastic and Reconstructive Surgery, Northwestern University Medical School, Chicago, Illinois 60611, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Galiano
authors.forename: L L
authors.initials: LL
authors.lastname: Zhao
authors.forename: D R
authors.initials: DR
authors.lastname: Clemmons
authors.forename: S I
authors.initials: SI
authors.lastname: Roth
authors.forename: X
authors.initials: X
authors.lastname: Lin
authors.forename: T A
authors.initials: TA
authors.lastname: Mustoe
mesh_terms: D000818:Animals; D001120:Arginine; D016466:CHO Cells; D003094:Collagen / Q000096:biosynthesis; D006224:Cricetinae; D004347:Drug Interactions; D005109:Extracellular Matrix / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D006025:Glycosaminoglycans / Q000096:biosynthesis; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000494:pharmacology*; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D009842:Oligopeptides; D017354:Point Mutation; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D012883:Skin Ulcer / Q000473:pathology / Q000503:physiopathology*; D014162:Transfection; D014364:Tryptophan; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
chemical_list: D016326:Extracellular Matrix Proteins; D006025:Glycosaminoglycans; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D009842:Oligopeptides; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; C047981:arginyl-glycyl-aspartic acid; D014364:Tryptophan; D003094:Collagen; D001120:Arginine