Connective Tissue Growth Factor as a Mediator of Intraocular Fibrosis

Fibrosis plays an important role in the pathogenesis of several common blinding disorders, including proliferative diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and PVR;1–4 however, much needs to be learned about the basic pathophysiology of fibrosis in the intraocular environment.1 PVR may be viewed as a prototypical example of a protracted intraocular wound healing response that occurs when traction-generating cellular membranes develop in the vitreous and on the inner or outer surfaces of the retina following rhegmatogenous retinal detachment or major ocular trauma.5–7 RPE cells play a critical role in this epiretinal membrane formation8,9 These cells proliferate and migrate from the RPE monolayer to form sheets of dedifferentiated cells within a provisional extracellular matrix (ECM) containing fibronectin and thrombospondin.9–11 The protracted wound healing response causes the cellular membrane to become progressively more paucicellular and fibrotic.11 Experimental models of PVR have been developed to evaluate intraocular proliferation;12–16 however, these models typically exhibit cellular fibrinous strands without prominent fibrotic responses. Studies evaluating the role of those factors that elicit this fibrotic response are of particular interest. Normal ocular wound healing involves a tightly coordinated series of events: recruitment and activation of inflammatory cells, release of cytokines and growth factors, activation, proliferation and migration of ocular cells, secretion of extracellular matrix, tissue remodeling, and repair.1, 17 CTGF is an important stimulant of fibrosis,18 but its role in intraocular wound healing or PVR has not been studied in detail. CTGF is a secreted, cysteine-rich, heparin-binding polypeptide growth factor,19 20 that is rapidly upregulated after stimulation with serum or transforming growth factor-β (TGF-β). Various CTGF fragments have been shown to accumulate in tissue culture or body fluids while retaining their biologic activity.20–22 CTGF functions as a downstream mediator of TGF- β action on fibroblasts; it stimulates cell proliferation and cell matrix deposition (collagen 1 and fibronectin),18,20,23 and it may induce apoptosis.24,25 In addition to its action as a growth factor, CTGF has been implicated as an adhesive substrate in fibroblasts, mediated through α6β1 integrin.26 Importantly, CTGF is coordinately expressed with TGF-β and it demonstrates increased expression in numerous fibrotic disorders, including systemic sclerosis,27,28 pulmonary, renal, and myocardial fibrosis,29–32 and atherosclerosis.33 In the present study, we examine the process by which CTGF mediates the transformation of activated RPE into a fibrotic epiretinal membrane. Our results identify CTGF as a major mediator of retinal fibrosis and potentially an effective therapeutic target.