title: Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury.
abstract: Lens epithelial cells undergo epithelial-mesenchymal transition (EMT) after injury as in cataract extraction, leading to fibrosis of the lens capsule. Fibrosis of the anterior capsule can be modeled in the mouse by capsular injury in the lens, which results in EMT of the lens epithelium and subsequent deposition of extracellular matrix without contamination of other cell types from outside the lens. We have previously shown that signaling via Smad3, a key signal-transducing element downstream of transforming growth factor (TGF)-beta and activin receptors, is activated in lens epithelial cells by 12 hours after injury and that this Smad3 activation is blocked by administration of a TGF-beta 2-neutralizing antibody in mice. We now show that EMT of primary lens epithelial cells in vitro depends on TGF-beta expression and that injury-induced EMT in vivo depends, more specifically, on signaling via Smad3. Loss of Smad3 in mice blocks both morphological changes of lens epithelium to a mesenchymal phenotype and expression of the EMT markers snail, alpha-smooth muscle actin, lumican, and type I collagen in response to injury in vivo or to exposure to exogenous TGF-beta in organ culture. The results suggest that blocking the Smad3 pathway might be beneficial in inhibiting capsular fibrosis after injury and/or surgery.
authors.affiliation: Department of Ophthalmology, Wakayama Medical University, Kimiidera, Wakayama, Japan. shizuya@wakayama-med.ac.jp
authors.forename: Shizuya
authors.initials: S
authors.lastname: Saika
authors.forename: Satoko
authors.initials: S
authors.lastname: Kono-Saika
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Ohnishi
authors.forename: Misako
authors.initials: M
authors.lastname: Sato
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Muragaki
authors.forename: Akira
authors.initials: A
authors.lastname: Ooshima
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Flanders
authors.forename: Jiyun
authors.initials: J
authors.lastname: Yoo
authors.forename: Mario
authors.initials: M
authors.lastname: Anzano
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Liu
authors.forename: Winston W-Y
authors.initials: WW
authors.lastname: Kao
authors.forename: Anita B
authors.initials: AB
authors.lastname: Roberts
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000502:physiology*; D005355:Fibrosis / Q000503:physiopathology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007908:Lens, Crystalline / Q000166:cytology* / Q000293:injuries / Q000473:pathology*; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein; D000071250:Snail Family Transcription Factors; D013552:Swine; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D000071250:Snail Family Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta