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exacerbation and subsequent contraction of fibrous tissue leading to tractional retinal detachment in patients who received anti-VEGF treatment for active PDR [140, 141]. PDR patients treated with bevacizumab also showed a remarkable inhibition of angiogenesis, suggesting that the elevated CTGF levels, which remain in the vitreous after VEGF inhibition, are not able to maintain the angiogenic response, providing further evidence that CTGF has no proangiogenic role in PDR.
As indicated, it appears from the available evidence that CTGF, in a critical balance with VEGF, drives the angiofibrotic switch and subsequent fibrosis in PDR. This indicates that CTGF-targeted therapy, in particular in combination with anti-VEGF agents, is a possible novel option to prevent sight-threatening fibrosis in PDR and other ocular diseases that are associated with neovascularization and fibrosis.
CONCLUSIONS
We conclude that in DR, CTGF has a role in two important stages of the disease. Early in the pathogenesis, CTGF contributes to thickening of the retinal capillary BL, which is a crucial step in the progression of DR. In this stage, CTGF interacts with AGEs, and growth factors such as VEGF and TGF-b are involved as well. Designing treatment strategies against TGF-b, a major inducer of fibrosis in many diabetic complications, is unfavorable, as this growth factor also exhibits (beneficial) immunosuppressive and anti-inflammatory activity. Targeting CTGF, a major regulator of profibrotic TGF-b action, may therefore be a much more suitable option in the preclinical stage of the disease.
In a later stage of the disease, the switch from neovascularization to a fibrotic phase in PDR is driven by CTGF, in a critical balance with VEGF. This indicates that CTGFtargeted therapy, in particular in combination with anti-VEGF agents, is a possible novel option to prevent sight-threatening fibrosis in PDR and other ocular diseases that are associated with neovascularization and fibrosis.
On the basis of these and other data, CTGF has been suggested to be useful as a biomarker for a wide range of fibrotic disorders [142]. A simple tool as ELISAs can be used to monitor the expression of CTGF and VEGF proteins in the vitreous of PDR patients, which enables the monitoring of disease progression and drug efficacy in clinical trials.
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Part IV
How Can Vision Loss Be Limited:
Experimental Therapies