1. ¹Department of Ophthalmology, Wakayama Medical University, Kimiidera, Wakayama, Japan
2. ²Department of Pathology, Wakayama Medical University, Kimiidera, Wakayama, Japan
3. ³Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Correspondence: Dr S Saika, MD, PhD, Department of Ophthalmology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-0012, Japan. E-mail: shizuya@wakayama-med.ac.jp

^*Current address: Department of Microbiology, Gyeongsang National University, Jinju 660-701, Korea and Research Institute of Life Science, Gyeongsang National University, Jinju, 660-701, Korea.

Received 29 May 2004; Accepted 10 June 2004; Published online 26 July 2004.

Abstract

Retinal pigment epithelial (RPE) cells dedifferentiate and undergo epithelial–mesenchymal transition (EMT) following retinal detachment, playing a central role in formation of fibrous tissue on the detached retina and vitreous retraction (proliferative vitreoretinopathy (PVR)). We have developed a mouse model of subretinal fibrosis with implications for PVR in which retinal detachment is induced without direct damage to the RPE cells. Transforming growth factor- (TGF-) has long been implicated both in EMT of RPEs and the development of PVR. Using mice null for Smad3, a key signaling intermediate downstream of TGF- and activin receptors, we show that Smad3 is essential for EMT of RPE cells induced by retinal detachment. De novo accumulation of fibrous tissue derived from multilayered RPE cells was seen following experimental retinal detachment in eyes of wild type, but not Smad3-null mice. Expression of -smooth muscle actin, a hallmark of EMT in this cell type, and extracellular matrix components, lumican and collagen VI, were also not observed in eyes of Smad3-null mice. Our data show that induction of PDGF-BB by Smad3-dependent TGF- signaling is likely an important secondary proliferative component of the disease process. The results suggest that blocking the Smad3 pathway might be beneficial in prevention/treatment of PVR.