P22 Fibrosis in delayed wound healing in diabetes: the role of insulin-like growth factor binding proteins

Abstract Skin fibrosis is thought to be a factor in delayed wound healing in people with diabetes. Insulin-like growth factor binding protein 5 (IGFBP-5), which is fibrotic in other organs, is augmented in the skin of people with diabetes. We examined the effects of IGFBP-5, connective tissue growth factor (CTGF) and transforming growth factor (TGF)-β1 on skin fibrosis and wound-healing capacity in human primary dermal fibroblasts from people with and without diabetes. In vitro scrape wound closure in diabetic dermal fibroblasts was delayed in diabetic fibroblasts. IGFBP-5 treatment further retarded scrape-wound closure rates above that seen with diabetic fibroblasts. Diabetic fibroblasts were more adhesive to substrates than normal fibroblasts in adhesion assays, reducing their migratory capacity, and normal fibroblasts treated with IGFBP-5 and TGF-β1 showed increased adhesion over controls. Diabetic fibroblasts also had reduced cell viability. Fibronectin and collagen production by fibroblasts were increased with IGFBP-5 in cultures; thus upregulated IGFBP-5 in diabetic skin may increase extracellular matrix (ECM) deposition. IGFBP-5 and α-smooth muscle actin protein was overexpressed in diabetic fibroblasts by Western blotting, so IGFBP-5 induces fibroblast to myofibroblast transition. Gene expression of matrix metalloproteinase (MMP)-1, MMP-9, CTGF and tissue inhibitor of metalloproteinase 1 (TIMP-1) was raised in diabetic fibroblasts; MMP-9, MMP-1 and TIMP-1 expression levels were increased with IGFBP-5 treatment. Elevated levels of IGFBP-5 and CGTF in the dermis may contribute to retarded wound healing and ulceration in people with diabetes (despite increases in fibroblast MMPs), causing fibroblasts to lay down more ECM, contributing to fibrosis and compromising the wound bed. Diabetic dermal fibroblasts are compromised in viability and migratory capacity, and are more adhesive and stiffer, making it more difficult for them to populate granulation tissue. They are thus less able to close wounds and hyperproliferate around wound edges. IGFBP-5 and CTGF could be novel therapeutic targets to mitigate diabetic skin fibrosis and improve wound healing.