Effects of IGFBP-1 and IGFBP-2 and their fragments on migration and IGF-induced proliferation of human dermal fibroblasts

Katrin Brandt; Jacob Grünler; Kerstin Brismar; Jing Wang

doi:10.1016/j.ghir.2014.11.001

Effects of IGFBP-1 and IGFBP-2 and their fragments on migration and IGF-induced proliferation of human dermal fibroblasts

Growth Horm IGF Res. 2015 Feb;25(1):34-40. doi: 10.1016/j.ghir.2014.11.001. Epub 2014 Nov 8.

Authors

Katrin Brandt¹, Jacob Grünler², Kerstin Brismar¹, Jing Wang¹

Affiliations

¹ Department of Molecular Medicine and Surgery, Karolinska Institute, Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
² 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.

PMID: 25468444
DOI: 10.1016/j.ghir.2014.11.001

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).

Design: 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.

Keywords: High glucose; IGF; IGFBP-1 and -2 IGFBP fragment; Migration; Proliferation; Special characters: α, β, μ.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Movement / drug effects*
Cell Proliferation / drug effects*
Cells, Cultured
Dermis / cytology
Fibroblasts / drug effects*
Humans
Insulin-Like Growth Factor Binding Protein 1 / pharmacology*
Insulin-Like Growth Factor Binding Protein 2 / pharmacology*
Insulin-Like Growth Factor I / pharmacology
Insulin-Like Growth Factor II / pharmacology
Peptide Fragments / pharmacology*

Substances

IGF1 protein, human
IGF2 protein, human
IGFBP1 protein, human
Insulin-Like Growth Factor Binding Protein 1
Insulin-Like Growth Factor Binding Protein 2
Peptide Fragments
Insulin-Like Growth Factor I
Insulin-Like Growth Factor II