The Functional Role of Decorin in Glaucoma
Final Report Abstract
In primary open-angle glaucoma (POAG), one of the leading causes of blindness, retinal ganglion cell death and axonal loss occur in the optic nerve head. Many prospective, randomized, multicenter studies have shown that inadequate intraocular pressure (IOP) is the most important risk factor for the development of this disease. In POAG, elevated IOP is caused by increased outflow resistance in the outflow pathway consisting of the trabecular meshwork and Schlemm's canal endothelium. The characteristic pathologic change in the outflow pathway of POAG patients is an accumulation of extracellular matrix (ECM) and increased contractility of the cells in this region. These changes are caused by a disturbance in the homeostatic balance of growth factors. Transforming growth factor (TGF)-β and connective tissue growth factor (CCN2/CTGF) are found at elevated levels in the aqueous humor of POAG patients and can cause pathologic changes in the outflow pathway. However, as these growth factors are also present in the aqueous humor and outflow pathway of healthy individuals, there must be endogenous antagonists that can prevent a shift in the balance toward pathology. In our studies, we identified decorin (DCN) as a novel endogenous antagonist of TGF-β2 and CCN2/CTGF. DCN is significantly reduced in the outflow tissues of POAG patients, and we have shown that DCN deficiency in mouse eyes leads to elevated IOP and axon loss in the optic nerve (ON) head, the hallmarks of the disease. IOP elevation was accompanied by increased synthesis of TGF-β2 and CCN2/CTGF, which increased ECM production in the outflow tissues. The in vitro studies demonstrated a reciprocal effect between DCN and the TGF-β2-CCN2/CTGF axis, suggesting a new therapeutic target for glaucoma patients. A better understanding of the biological function of CCN2/CTGF is necessary to gain insight to target the negative effects of this growth factor. In an additional study we demonstrated that CCN2/CTGF is expressed in many ocular tissues, but mainly in glaucoma relevant cells such as trabecular meshwork and Schlemm's canal endothelium, but also in retinal astrocytes and Müller glial cells. Very strong promoter activity was observed in astrocytes of the glial lamina at the ON head. This finding led to the hypothesis that loss of DCN would also have a negative effect in the ON head. Indeed, in another study, we were able to show that DCN is predominantly expressed by astrocytes in the ON, especially in the glial lamina. The in vitro studies showed again the reciprocal effect between these proteins and that DCN mediates its effects via pAKT/Akt signaling. In a follow-up study, we showed that CCN2/CTGF is upregulated in the ON head of POAG patients and that stiffening of the surrounding tissues lead to an additional increased production of CCN2/CTGF by ON astrocytes. Such a scenario may finally result in a vicious circle in the pathogenesis of POAG.
Publications
-
A novel ocular function for decorin in the aqueous humor outflow. Matrix Biology, 97, 1-19.
Schneider, Magdalena; Pawlak, Ramona; Weber, Gregor R.; Dillinger, Andrea E.; Kuespert, Sabrina; Iozzo, Renato V.; Quigley, Harry A.; Ohlmann, Andreas; Tamm, Ernst R. & Fuchshofer, Rudolf
-
CCN2/CTGF promotor activity in the developing and adult mouse eye. Cell and Tissue Research, 384(3), 625-641.
Dillinger, Andrea E.; Kuespert, Sabrina; Froemel, Franziska; Tamm, Ernst R. & Fuchshofer, Rudolf
-
Decorin—An Antagonist of TGF-β in Astrocytes of the Optic Nerve. International Journal of Molecular Sciences, 22(14), 7660.
Schneider, Magdalena; Dillinger, Andrea E.; Ohlmann, Andreas; Iozzo, Renato V. & Fuchshofer, Rudolf
-
ISER/BrightFocus Glaucoma Symposium 2021: Concepts and Breakthroughs in Glaucoma; Atlanta, Georgia, USA; Vortrag: DECORIN – AN ANTAGONIST OF TGF-Β IN ASTROCYTES OF THE OPTIC NERVE.
Fuchshofer, Rudolf
-
CCN2/CTGF—A Modulator of the Optic Nerve Head Astrocyte. Frontiers in Cell and Developmental Biology, 10.
Dillinger, Andrea E.; Weber, Gregor R.; Mayer, Matthias; Schneider, Magdalena; Göppner, Corinna; Ohlmann, Andreas; Shamonin, Mikhail; Monkman, Gareth J. & Fuchshofer, Rudolf
