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P<P, published online ahead of print April 30, 2008
(Investigative Ophthalmology and Visual Science. )
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-1302
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Article

Connective Tissue Growth Factor as a Mediator of Intraocular Fibrosis

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

1 Pathology, Keck School of Medicine of USC, Los Angeles, California, United States
2 Ophthalmology, Peking Union Medical College, Beijing, China
3 Doheny Eye Institute, Los Angeles, California, United States
4 Fibrogen Inc, South San Francisco, California, United States
5 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, 90033, United States

* To whom correspondence should be addressed. E-mail: dhinton{at}hsc.usc.edu.


  Abstract

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, while 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, while migration was assayed with a Boyden chamber assay. Experimental PVR was induced in rabbits using 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 expressing CTGF. Results: CTGF was highly expressed in human PVR membranes and partially co-localized with cytokeratin-positive RPE cells. Treatment of RPE with rhCTGF stimulated migration with a peak response at 50ng/ml (P<0.05), and increased expression of type I collagen (P<0.05). There was a prominent accumulation of N-terminal half of CTGF in the vitreous of patients with PVR. Intravitreal injection of rhCTGF alone did not produce PVR, while such injections into rabbits with mild, nonfibrotic PVR promoted the development of dense, fibrotic epiretinal membranes. Similarly, intravitreal injection of RPE cells infected with adenoviral vectors overexpressing CTGF induced fibrotic PVR. Experimental PVR was associated with increased CTGF mRNA in PVR membranes and accumulation of CTGF half fragments in vitreous. Conclusion: Our results identify CTGF as a major mediator of retinal fibrosis and potentially an effective therapeutic target for PVR.

Key Words: retinal pigment epithelium, growth factors, vitreoretinopathy, connective tissue growth factor, fibrosis






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