title: Effects of IGFBP-1 and IGFBP-2 and their fragments on migration and IGF-induced proliferation of human dermal fibroblasts.
abstract: OBJECTIVE
  A family of six insulin-like growth factor (IGF) binding-proteins (IGFBP) bind to IGF-I and IGF-II with high affinity and modulate their activity. We have recently shown that a neutrophil-derived protease activity cleaved IGFBP-1, -2 and -4. IGFBP-1 and IGFBP-2 have a C-terminal Arg-Gly-Asp (RGD) sequence, and IGFBP-1 has been shown by others to stimulate migration through binding of its RGD sequence to α5β1 integrin. The aim of this study was to determine the effect of this IGFBP protease on IGF-induced proliferation and the effect of IGFBP-1 and IGFBP-2 and their proteolytic fragments on migration in normal and high glucose of human dermal fibroblasts (HDF).
  
  
  METHODS
  We investigated the effect of intact or cleaved IGFBP-1 and -2 on proliferation in cultured HDFs and on HDF migration in normal and high glucose.
  
  
  RESULTS
  Both IGFBP-1 and IGFBP-2 and their proteolytic fragments stimulated HDF migration and the stimulatory effect was abolished by pre-treating cells with a α5β1 integrin antibody. High glucose impaired migration of HDFs; however, the addition of IGFBP-1, IGFBP-2 or fragments increased migration to levels observed in normoglycemia. IGFBP-2 inhibited IGF-II induced proliferation; however, the inhibitory effect was reduced after being cleaved. Intact native IGFBP-1 showed either potentiating or inhibitory effects on IGF-I induced proliferation depending on the confluence of cells, and proteolysis of IGFBP-1 did not change these effects. IGFBP-1 was found to increase phosphorylation of FAK and ERK1/2 and this effect was inhibited by the monoclonal integrin a5β1 ab.
  
  
  CONCLUSIONS
  IGFBP-1 and -2 and their proteolytic fragments may improve tissue repair under inflammatory conditions, through effects on proliferation and migration of HDFs in normal and high glucose.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Katrin
authors.initials: K
authors.lastname: Brandt
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden. Electronic address: Jacob.Grunler@ki.se.
authors.forename: Jacob
authors.initials: J
authors.lastname: Grünler
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brismar
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects*; 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; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*
chemical_list: C583557:IGF1 protein, human; C035170:IGF2 protein, human; C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D010446:Peptide Fragments; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II
keywords: High glucose; IGF; IGFBP-1 and -2 IGFBP fragment; Migration; Proliferation; Special characters: α, β, μ