Minireview: Fibronectin in retinal disease

Abstract

Retinal fibrosis, characterized by dysregulation of extracellular matrix (ECM) protein deposition by retinal endothelial cells, pigment epithelial cells, and other resident cell-types, is a unifying feature of several common retinal diseases. Fibronectin is an early constituent of newly deposited ECM and serves as a template for assembly of other ECM proteins, including collagens. Under physiologic conditions, fibronectin is found in all layers of Bruch's membrane. Proliferative vitreoretinopathy (PVR), a complication of retinal surgery, is characterized by ECM accumulation. Among the earliest histologic manifestations of diabetic retinopathy (DR) is capillary basement membrane thickening, which occurs due to perturbations in ECM homeostasis. Neovascularization, the hallmark of late stage DR as well as exudative age-related macular degeneration (AMD), involves ECM assembly as a scaffold for the aberrant new vessel architecture. Rodent models of retinal injury demonstrate a key role for fibronectin in complications characteristic of PVR, including retinal detachment. In mouse models of DR, reducing fibronectin gene expression has been shown to arrest the accumulation of ECM in the capillary basement membrane. Alterations in matrix metalloproteinase activity thought to be important in the pathogenesis of AMD impact the turnover of fibronectin matrix as well as collagens. Growth factors involved in PVR, AMD, and DR, such as PDGF and TGFβ, are known to stimulate fibronectin matrix assembly. A deeper understanding of how pathologic ECM deposition contributes to disease progression may help to identify novel targets for therapeutic intervention.

Keywords: Fibronectin; age-related macular degeneration; diabetic retinopathy; extracellular matrix; fibrosis; neovascularization; proliferative vitreoretinopathy; retina.

Figure 1

Fibronectin. Fibronectin is a multi-domain glycoprotein consisting of 3 different modules (types I, II, and III) comprising several binding sites including an FN self-association domain, collagen-binding domain, cell-binding domain, and heparin-binding domain. Three alternatively spliced regions include the extra domain-A (EDA) and EDB regions, both type III repeats, and a variable (V) region. The protein is secreted as a dimer, linked by disulfide bonds (adapted from Mao and Schwarzbauer). (A color version of this figure is available in the online journal.)

Figure 2

Anatomy of the retina. The thin sheet of neural tissue that comprises the retina lines the globe of the eye, overlying the retinal pigment epithelium (RPE), Bruch’s membrane, and the vessels of the choroid. The sclera is a connective tissue layer that encases all of these structures. The macula is the portion of the retina responsible for central vision, owing to the high concentration of cone cells within the fovea – a depression within the macula (adapted from Yuan et al.). (A color version of this figure is available in the online journal.)