Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury.
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.
Saika
Shizuya
S
Department of Ophthalmology, Wakayama Medical University, Kimiidera, Wakayama, Japan. shizuya@wakayama-med.ac.jp
Kono-Saika
Satoko
S
Ohnishi
Yoshitaka
Y
Sato
Misako
M
Muragaki
Yasuteru
Y
Ooshima
Akira
A
Flanders
Kathleen C
KC
Yoo
Jiyun
J
Anzano
Mario
M
Liu
Chia-Yang
CY
Kao
Winston W-Y
WW
Roberts
Anita B
AB
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
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