Abstract
Fundamental cell signaling mechanisms that regulate dynamic remodeling of the extracellular matrix (ECM) in mechanically loaded tissues are not yet clearly understood. Trabecular meshwork (TM) tissue in the eye is under constant mechanical stress and continuous remodeling of ECM is crucial to maintain normal aqueous humor drainage and intraocular pressure (IOP). However, excessive ECM remodeling can cause fibrosis of the TM as in primary open-angle glaucoma (POAG) patients, and is characterized by increased resistance to aqueous humor drainage, elevated IOP, optic nerve degeneration and blindness. Increased levels of active transforming growth factor-β2 (TGF-β2) in the aqueous humor is the main cause of fibrosis of TM in POAG patients. Herein, we report a novel finding that, in TM cells, TGF-β-induced increase in collagen expression is associated with phosphorylation of phosphatase and tensin homolog (PTEN) at residues Ser380/Thr382/383. Exogenous overexpression of a mutated form of PTEN with enhanced phosphatase activity prevented the TGF-β-induced collagen expression by TM cells. We propose that rapid alteration of PTEN activity through changes in its phosphorylation status could uniquely regulate the continuous remodeling of ECM in the normal TM. Modulating PTEN activity may have high therapeutic potential to alleviating the fibrosis of TM in POAG patients.
Highlights
One of the factors that has a major impact on excess extracellular matrix (ECM) deposition in many fibrotic diseases is transforming growth factor-beta (TGF-β)[3]
Since our results are consistent with the hypothesis that TGF-β regulates collagen deposition by modulating Phosphatase and tensin homolog (PTEN)/AKT levels and phosphorylation, we further investigated whether inhibition of PTEN activity and its overexpression affected collagen expression by trabecular meshwork (TM) cells
TGF-β is a well-established inducer of collagen deposition by activation of canonical Smads and through non-canonical PI3-kinase and p38 MAPK signaling pathways[49,50,51,52, 58, 59]
Summary
One of the factors that has a major impact on excess ECM deposition in many fibrotic diseases is transforming growth factor-beta (TGF-β)[3]. Further investigation are required to delineate fundamental regulatory feed-back signaling mechanisms that could prevent fibrotic actions of TGF-β without affecting its normal homeostatic roles in tissues. Such signaling mechanisms when identified may serve as effective therapeutic targets to prevent disease-associated fibrosis. PTEN is known to dephosphorylate focal-adhesion kinase, and Src homology 2 domain containing transforming protein[21] By regulating these signaling pathways, PTEN is able to modulate multiple cellular activities, including contractility, survival, apoptosis, migration and, cell-ECM interaction and signaling[21]. One strategy to lower the IOP is to prevent the fibrosis of the TM; this has not yet been accomplished[35]
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