TGFβ2-Induced Changes in Human Trabecular Meshwork: Implications for Intraocular Pressure

Abstract

TGFbeta2 effects on IOP may be transduced by TGFbeta type-I receptor-mediated changes in TM secretion of ECM-related factors such as fibronectin and PAI-1. Modulation of TGFbeta2-induced changes in the ECM may provide a novel and viable approach to the management of glaucoma.

Extracellular matrix in the trabecular meshwork

“…(Tripathi et al 1991;Si et al 2003;FlugelKoch et al 2004;Zhao et al 2004;Chen et al 2005;Fleenor et al 2006;Liton et al 2006;Fuchshofer et al 2007) Figure 7 shows the domain structures and binding motifs of the thrombospondins. Thrombospondins 1 and 2 form homotrimeric structures and are considered to be matricellular proteins, while thrombospondins 3 and 4 are structurally somewhat different and are not considered to be matricellular proteins.…”

“…(Parks and Mecham 1998) These stimuli include TNFα, IL-1α, TGFβ, dexamethasone, elevated pressure, and/or mechanical stretch. (Samples et al 1993;Clark et al 1995b;Alexander et al 1998;Bradley et al 1998;Bradley et al 2000;Bradley et al 2001;Gottanka et al 2004;Chen et al 2005;Clark et al 2005;Vittal et al 2005;Fleenor et al 2006;Kelley et al 2007) The process of ECM turnover is a concerted and highly coordinated program of degradation and biosynthetic replacement of specific ECM components. IOP homeostasis appears to be maintained, at lease in part by ECM turnover triggered in response to pressure changes or mechanical stretch or distortion, sensed by cells within the JCT.…”

“…(Tripathi, RC et al 1994) TGFβ2 perfusion reduces outflow facility and is generally thought to increase ECM production. (Gottanka et al 2004;Fleenor et al 2006) In TM cells, a number of ECM genes are modulated by TGFβ1 and/or TGFβ2 (Table 3). (Zhao et al 2004;Fleenor et al 2006) Earlier, it was shown that TGFβ1 β2, β3 and β5 all increased MMP-3 expression by the TM.…”

“…(Gottanka et al 2004;Fleenor et al 2006) In TM cells, a number of ECM genes are modulated by TGFβ1 and/or TGFβ2 (Table 3). (Zhao et al 2004;Fleenor et al 2006) Earlier, it was shown that TGFβ1 β2, β3 and β5 all increased MMP-3 expression by the TM. (Alexander et al 1998) In addition to these and many other changes observed, versican splicing was affected, as discussed later.…”

Bioactive Lysophospholipids: Role in Regulation of Aqueous Humor Outflow and Intraocular Pressure in the Context of Pathobiology and Therapy of Glaucoma

“…[23][24][25][26][27][28] A great deal of effort has gone into exploring how these different bioactive agents influence TM tissue properties and cell biology in the context of AH outflow in both in vitro and in vivo studies. 15,16,24,[29][30][31][32][33][34][35][36] These efforts are beginning to unravel the participation of several different intracellular signaling mechanisms, including Rho GTPase, Wnt, ECM/ mechanotransduction, integrins, nitric oxide, PKC, BMPs/ SMADs, MAP kinases, and others, in regulating contractile properties of TM cells, ECM turnover, adhesive interactions, biomechanical properties, permeability, and survival of outflow pathway tissues and cells. 14,24,[37][38][39][40] These different observations offer significant insights into the regulation of AH outflow and suggest several novel avenues to target selected signaling pathways and other molecular targets for increasing AH outflow through the conventional pathway, and for the development of new and mechanism-based IOP lowering drugs.…”