A novel ocular function for decorin in the aqueous humor outflow

Decorin—An Antagonist of TGF-β in Astrocytes of the Optic Nerve

“…The biological effect of DCN was discovered by its abilities to interact with growth factors and receptor tyrosine kinases as well [35][36][37][38]. A vital role of DCN within the eye was proven as a mutation in the DCN gene causes congenital stromal corneal dystrophy [39,40] and lack of DCN leads to a glaucomatous phenotype in DCN-deficient mice, which fits to the observations that DCN is found in reduced amounts in the aqueous humor and in the outflow tissues of POAG patients [32,41,42]. Since the ON and ONH undergo changes during the course of POAG, which are most likely due to elevated levels of TGF-β and CTGF/CCN2, we tested the hypothesis if the presence or absence of DCN would also affect the expression of the TGF-βs and CTGF/CCN2 in the ON and ONH.…”

“…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 ]. Analysis of mRNA levels of ONs obtained from DCN-deficient mice and their wildtype (WT) littermates revealed an upregulation of TGF-β2 (WT = 1 ± 0.13, n = 9, Dcn −/− = 1.85 ± 0.23, n = 10, p = 0.036), TGF-β1 (WT = 1 ± 0.15, n = 9, Dcn −/− = 1.83 ± 0.23, n = 10, p = 0.040) as well as CTGF/CCN2 (WT = 1 ± 0.15, n = 7, Dcn −/− = 1.84 ± 0.23, n = 7, p = 0.044) ( Figure 1 A).…”

“…Alterations in the ECM arrangement of the lamina cribrosa and the peripapillary sclera cause changes in the mechanical support of this region and thereby affect the mechanosensation mechanisms of astrocytes by their junctional complexes upon IOP elevation [55]. In DCN-deficient mice we reported previously that the increase in IOP and the loss of ON axons is accompanied by an enhanced expression and synthesis of GFAP by astrocytes [32], which, from a biomechanical perspective, would cause together with ECM changes an increase in tissue stiffness [62,63]. Up to now, there has been no data on the amounts of DCN in the ONH of glaucoma patients, which would be of great interest since increased amounts of TGF-β are known to be present in the ONH [26,28,47] DCN can influence the activity and expression of TGF-β via different pathways, firstly via direct binding [64] and secondly via the upregulation of fibrillin-1 (FBN1) synthesis.…”

“…TGF-β treatment leads to a decreased DCN expression in human skin fibroblasts and human chondrocytes [ 52 , 53 ] while DCN expression is upregulated after TGF-β treatment in murine osteoblasts and rat mesangial cells [ 54 ]. Recently we could demonstrate that TGF-β2 and DCN as well as CTGF/CCN2 and DCN have negative reciprocal effects on mRNA expression and protein synthesis in the TM in vitro and in vivo [ 32 ]. In murine ON astrocytes and human ONH astrocytes, treatment with CTGF/CCN2 and TGF-β2 caused a significant reduction in DCN mRNA expression, whereas only CTGF/CCN2 led to a significant reduction of DCN synthesis in both cell lines.…”

“…We have recently discovered that decorin (DCN) is a key modulator of the TGF-β2 and CTGF/CCN2 activities in the outflow tissues. DCN was initially described as a regulator of collagen fibrillogenesis [ 32 , 33 , 34 ], but like other small leucine-rich proteoglycans, the biological function of DCN extends beyond the interaction with collagens. The biological effect of DCN was discovered by its abilities to interact with growth factors and receptor tyrosine kinases as well [ 35 , 36 , 37 , 38 ].…”