The role of connective tissue growth factor in diabetic retinopathy

    Recently we demonstrated an important role of connective tissue growth factor (CTGF) in the development of different stages of DR. CTGF was not only found to play a role in fibro-vascular proliferation in proliferative DR (PDR),^{1, 2} but also in basement membrane thickening in PCDR.^3-5 Different cell types in the retina seem to be involved. CTGF protein expression shifts from microglia to microvascular pericytes in the progression of human DR.⁶ CTGF is an important downstream mediator of the pro-fibrotic effects of transforming growth factor-β (TGF-β) operative in the maintenance and repair of connective tissues and in the setting of fibrotic diseases. As regulation by TGF-β is complex and both cell/tissue specific and context/stage dependent, CTGF is amore attractive and selective therapeutic target.

    Vascular endothelial growth factor-A (VEGF) has a major role in DR, causing both vascular leakage and angiogenesis.⁷ Our own results indicate that the balance between fibrogenic and angiogenic processes in the eye is correlated with the CTGF/VEGF ratio.² Whereas CTGF levels were predominant over VEGF levels in fibrotic eye diseases, VEGF levels were relatively higher in eye diseases with neovascularisation. This indicates that the equilibrium of VEGF and CTGF is important for the normal healthy situation and an imbalance of these factors leads to disease.   

     In diabetic CTGF-heterozygous mice, we found that reduced CTGF expression was not associated with reduced angiogenesis,⁸ but with reduced capillary basement membrane thickening in the retinal capillaries and the glomerulus.^{5, 9} This suggests that CTGF is necessary for basement membrane thickening. We found more support for this hypothesis in other recent studies in two experimental models of PCDR (streptozotocin(STZ)-induced diabetes and retinopathy induced by high ocular VEGF levels). In these models, elevated CTGF mRNA and protein levels coincided with elevated levels of extracellular matrix genes involved in basement membrane synthesis and inhibition of basement membrane breakdown.^3,4

1. Kuiper EJ, de Smet MD, van Meurs JC, Tan HS, Tanck MW, Oliver N, van Nieuwenhoven FA, Goldschmeding R, Schlingemann RO. Association of connective tissue growth factor with fibrosis in vitreoretinal disorders in the human eye. Arch Ophthalmol. 2006;124(10):1457-62.

2. Kuiper EJ, Van Nieuwenhoven FA, de Smet MD, van Meurs JC, Tanck MW, Oliver N, Klaassen I, Van Noorden CJ, Goldschmeding R, Schlingemann RO. The angio-fibrotic switch of VEGF and CTGF in proliferative diabetic retinopathy. PLoS ONE. 2008 Jul 16;3(7):e2675.

3. Kuiper EJ, Hughes JM, Van Geest RJ, Vogels IM, Goldschmeding R, Van Noorden CJ, Schlingemann RO, Klaassen I. Effect of VEGF-A on expression of profibrotic growth factor and extracellular matrix genes in the retina. Invest Ophthalmol Vis Sci. 2007;48(9):4267-76.

4. Hughes JM, Kuiper EJ, Klaassen I, Canning P, Stitt AW, Van Bezu J, Schalkwijk CG, Van Noorden CJ, Schlingemann RO. Advanced glycation end products cause increased CCN family and extracellular matrix gene expression in the diabetic rodent retina. Diabetologia. 2007;50(5):1089-98.

5. Kuiper EJ, van Zijderveld R, Roestenberg P, Lyons KM, Goldschmeding R, Klaassen I, Van Noorden CJ, Schlingemann RO. Connective tissue growth factor is necessary for retinal capillary Basal lamina thickening in diabetic mice. J Histochem Cytochem. 2008 Aug;56(8):785-92.

6. Kuiper EJ, Witmer AN, Klaassen I, Oliver N, Goldschmeding R, Schlingemann RO. Differential expression of connective tissue growth factor in microglia and pericytes in the human diabetic retina. Br J Ophthalmol. 2004 Aug;88(8):1082-7.

7. Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO. Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res. 2003;22(1):1-29. Review.

8. Kuiper EJ, Roestenberg P, Ehlken C, Lambert V, van Treslong-de Groot HB, Lyons KM, Agostini HJ, Rakic JM, Klaassen I, Van Noorden CJ, Goldschmeding R, Schlingemann RO. Angiogenesis is not impaired in connective tissue growth factor (CTGF) knock-out mice. J Histochem Cytochem. 2007;55(11):1139-47.

9.    Roestenberg P, Van Nieuwenhoven FA, Goldschmeding R. Possible mechanisms of CTGF action in the pathogenesis of diabetes-induced GBM thickening. In: Roestenberg P. The role of CTGF in Diabetic Nephropathy. Marker, pathogenic factor and target for therapeutic intervention. PhD Thesis. Ipskamp, Enschede, The Netherlands; 2007, Chapter 8: p.137-55.