IOVS Hypertension
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Originally published In Press as doi:10.1167/iovs.07-1302 on April 30, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:4078-4088.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-1302
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Connective Tissue Growth Factor as a Mediator of Intraocular Fibrosis

Shikun He,1,2,3,4 Youxin Chen,3,4 Rima Khankan,1 Ernesto Barron,3 Richard Burton,3 DanHong Zhu,1,3 Stephen J. Ryan,2,3 Noelynn Oliver,5 and David R. Hinton1,2,3

1From the Departments of Pathology and 2Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California; the 3Doheny Eye Institute, Los Angeles, California; and 5FibroGen, Inc., South San Francisco, California.

PURPOSE. To investigate the role of connective tissue growth factor (CTGF) in the pathogenesis of proliferative vitreoretinopathy (PVR).

METHODS. Expression of CTGF was evaluated immunohistochemically in human PVR membranes, and the accumulation of CTGF in the vitreous was evaluated by ELISA. The effects of CTGF on type I collagen mRNA and protein expression in RPE were assayed by real-time PCR and ELISA, and migration was assayed with a Boyden chamber assay. Experimental PVR was induced in rabbits with vitreous injection of RPE cells plus rhCTGF; injection of RPE cells plus platelet derived-growth factor, with or without rhCTGF, or by injection of RPE cells infected with an adenoviral vector that expressed CTGF.

RESULTS. CTGF was highly expressed in human PVR membranes and partially colocalized with cytokeratin-positive RPE cells. Treatment of RPE with rhCTGF stimulated migration with a peak response at 50 ng/mL (P < 0.05) and increased expression of type I collagen (P < 0.05). There was a prominent accumulation of the N-terminal half of CTGF in the vitreous of patients with PVR. Intravitreous injection of rhCTGF alone did not produce PVR, whereas such injections into rabbits with mild, nonfibrotic PVR promoted the development of dense, fibrotic epiretinal membranes. Similarly, intravitreous injection of RPE cells infected with adenoviral vectors that overexpress CTGF induced fibrotic PVR. Experimental PVR was associated with increased CTGF mRNA in PVR membranes and accumulation of CTGF half fragments in the vitreous.

CONCLUSIONS. The results identify CTGF as a major mediator of retinal fibrosis and potentially an effective therapeutic target for PVR.






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