Cytoskeleton Regulators in the Control of Corneal Fibrosis

Abstract

Purpose: Corneal fibrosis is the third leading cause of blindness world-wide. a-smooth muscle actin (SMA), a marker of fibrosis, are closely regulated through an intermediate group of sub-membrane molecules - cytoskeletal regulators The purpose of this study was to elucidate the role of specific cytoskeletal regulators in a mouse model of corneal fibrosis. Methods: A mouse model of corneal fibrosis was developed using the anterior keratectomy (AK) and the topical application of transforming growth factor (TGF)-?1 (1?g/ml). The RT? Profiler? PCR Array for cytoskeleton regulators was used to assay changes in levels of specific members of this class of proteins. Moesin siRNA was delivered into the corneal stroma by iontophoresis in vivo. Transformation of the corneal keratocyte-to-myofibroblast in the corneal fibrosis, as defined by the expression of a-SMA, was determined by western blot. Results: After AK and topical application of TGF-?1, moesin was the most highly up-regulated gene among 84 cytoskeleton regulator genes; iontophoresing moesin siRNA into the corneal stroma reduced the expression of a-SMA to 0.22-, 0.52-, and 0.31- fold of control at PO day 1, 3, and 5 respectively; also, up-regulation of phospho-Smad 2 induced by TGF-?1 was reduced by moesin siRNA to 0.59-, 0.56-, and 0.31-fold of control and expression of phospho-Smad 3 was reduced to 0.58-, 0.53-, and 0.47-fold of control at the same PO days. Conclusions: Moesin may be a potential drug target for inhibiting corneal fibrosis and the details of moesin-related signaling pathways would be critical for understanding corneal fibrosis.