Abstract
During the pathogenesis of glaucoma, optic nerve (ON) axons become continuously damaged at the optic nerve head (ONH). This often is associated with reactive astrocytes and increased transforming growth factor (TGF-β) 2 levels. In this study we tested the hypothesis if the presence or absence of decorin (DCN), a small leucine-rich proteoglycan and a natural inhibitor of several members of the TGF family, would affect the expression of the TGF-βs and connective tissue growth factor (CTGF/CCN2) in human ONH astrocytes and murine ON astrocytes. We found that DCN is present in the mouse ON and is expressed by human ONH and murine ON astrocytes. DCN expression and synthesis was significantly reduced after 24 h treatment with 3 nM CTGF/CCN2, while treatment with 4 pM TGF-β2 only reduced expression of DCN significantly. Conversely, DCN treatment significantly reduced the expression of TGF-β1, TGF-β2 and CTGF/CCN2 vis-a-vis untreated controls. Furthermore, DCN treatment significantly reduced expression of fibronectin (FN) and collagen IV (COL IV). Notably, combined treatment with DCN and triciribine, a small molecule inhibitor of protein kinase B (AKT), attenuated effects of DCN on CTGF/CCN2, TGF-β1, and TGF-β2 mRNA expression. We conclude (1) that DCN is an important regulator of TGF-β and CTGF/CCN2 expression in astrocytes of the ON and ONH, (2) that DCN thereby regulates the expression of extracellular matrix (ECM) components and (3) that DCN executes its negative regulatory effects on TGF-β and CTGF/CCN2 via the pAKT/AKT signaling pathway in ON astrocytes.
Highlights
We discovered that DCN is produced by human optic nerve head (ONH) astrocytes and murine astrocytes of the optic nerve (ON) and that DCN deficiency leads to an upregulation of TGF-β and CTGF/CCN2 in the murine ON
While we found that TGF-β2 and CTGF/CCN2 reduce the expression of DCN, we could prove that DCN negatively regulates TGF-β2 and CTGF/CCN2 via the pAKT/AKT pathway and that DCN is able to reduce expression of the extracellular matrix (ECM) components FN and collagen IV (COL IV) in human ONH astrocytes and murine ON astrocytes
We previously reported that the absence of DCN leads to a glaucomatous phenotype in mice, with an increased expression of growth factors and ECM components in the region of the trabecular meshwork (TM) [32]
Summary
The second leading cause of blindness worldwide, is a neurodegenerative disorder due to a progressive degeneration of the optic nerve (ON) [1,2]. Up to 127 gen loci associated with glaucoma could be identified in genome-wide association studies, showing a strong genetic predisposition to this disease [3,4]. Prospective randomized multicenter studies have identified intraocular pressure (IOP) as the main critical risk factor for onset and progression of primary open-angle glaucoma (POAG), the most frequent form of glaucoma [5,6,7,8,9]. Axonal transport is impaired due to the effects of mechanical stress induced by IOP on the peripapillary sclera and the optic nerve head (ONH), causing the injury and death of retinal ganglion cells (RGC) [10]
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