The Insulin-Like Growth Factor System Modulates Retinal Pigment Epithelial Cell Tractional Force Generation

Abstract

The goal of this study was to determine the influence, if any, of the insulin-like growth factors (IGFs) on retinal pigment epithelial (RPE) cell tractional force generation and the contributions of vitreous insulin-like growth factor-binding proteins (IGFBPs) toward control of growth factor activity. IGF effects on RPE were evaluated in tissue culture assays that involved incubation on three-dimensional collagen matrices with responses measured as progressive reduction in matrix thickness. IGFBP effects were evaluated by using the same system, exposing cells to a non-IGFBP-binding growth factor analogue (R(3)IGF-I) or IGFBPs alone or in combination with native growth factors. RPE cells generated tractional forces in response to IGF-I and -II with IGF-I being the more potent stimulus. Differential RPE responses to R(3)IGF-I reflected minor amounts of endogenous IGFBP production. IGFBP-2, -3, and -5 were effective inhibitors of both ligands, whereas IGFBP-6 reduced cell responses to IGF-II only. IGFBP-direct effects on the cells were binding-protein-specific, in that IGFBP-1 had detectable stimulatory effects, and IGFBP-3, -4, -5, and -6 inhibited RPE responses. IGF-I and -II are potent promoters of RPE cell tractional force generation in vitro. The effects of the six high-affinity IGFBPs on RPE responses are generally inhibitory and protein-specific. IGF ligands and binding proteins are known to be present in the vitreous, the environment that drives RPE responses in proliferative vitreoretinopathy (PVR), suggesting that the IGF system plays a potentially important role in the pathophysiology of this fibrocontractive disease.