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Accumulation of NH₂-Terminal Fragment of Connective Tissue Growth Factor in the Vitreous of Patients With Proliferative Diabetic Retinopathy

¹ Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California
² Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California
³ Beckman Macular Research Center at the Doheny Eye Institute, Los Angeles, California
⁴ FibroGen, South San Francisco, California
⁵ Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California

Address correspondence and reprint requests to David R. Hinton, MD, Department of Pathology, Keck School of Medicine, 2011 Zonal Ave., HMR 209, Los Angeles, CA 90033. E-mail: dhinton{at}usc.edu

OBJECTIVE—To evaluate the expression of connective tissue growth factor (CTGF) and its fragments in the vitreous of patients with proliferative diabetic retinopathy (PDR) and to localize CTGF expression in associated preretinal membranes.

RESEARCH DESIGN AND METHODS—Vitreous was obtained from 24 patients with active PDR, 4 patients with quiescent PDR, and 23 patients with other retinal diseases and no diabetes, including 5 patients with vitreous hemorrhage. Enzyme-linked immunosorbent assay was used to determine levels of whole CTGF and its NH₂- and COOH-terminal fragments. Preretinal membranes from three patients with active PDR were stained immunohistochemically for the presence of CTGF and cell type-specific markers.

RESULTS—A significant increase in NH₂-terminal CTGF fragment content was found in vitreous samples from patients with active PDR when compared with samples from nondiabetic patients (P < 0.0001) or patients with quiescent PDR (P = 0.02). Levels of NH₂-terminal CTGF were also greater in vitreous samples from diabetic patients with vitreous hemorrhage compared with samples from nondiabetic patients with vitreous hemorrhage (P = 0.02). Vitreous levels of whole CTGF were similar in all groups. COOH-terminal fragments of CTGF were not detected. CTGF immunoreactivity was predominantly localized to smooth muscle actin-positive myofibroblasts within active PDR membranes.

CONCLUSIONS—NH₂-terminal CTGF fragment content is increased in the vitreous of patients with active PDR, suggesting that it plays a pathogenic role or represents a surrogate marker of CTGF activity in the disorder. The localization of CTGF in myofibroblasts suggests a local paracrine mechanism for induction of fibrosis and neovascularization.

Abbreviations: CTGF, connective tissue growth factor • ELISA, enzyme-linked immunosorbent assay • MMP, matrix metalloproteinase • PDR, proliferative diabetic retinopathy • rhCTGF, recombinant human CTGF • SMA, smooth muscle actin • TGF, transforming growth factor • VEGF, vascular endothelial growth factor

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