title: FGF2 antagonizes aberrant TGFβ regulation of tropomyosin: role for posterior capsule opacity.
abstract: Transforming growth factor (TGF) β2 and fibroblast growth factor (FGF) 2 are involved in regulation of posterior capsule opacification (PCO) and other processes of epithelial-mesenchymal transition (EMT) such as cancer progression, wound healing and tissue fibrosis as well as normal embryonic development. We previously used an in vivo rodent PCO model to show the expression of tropomyosin (Tpm) 1/2 was aberrantly up-regulated in remodelling the actin cytoskeleton during EMT. In this in vitro study, we show the Tpms family of cytoskeleton proteins are involved in regulating and stabilizing actin microfilaments (F-actin) and are induced by TGFβ2 during EMT in lens epithelial cells (LECs). Importantly, we found TGFβ2 and FGF2 played contrasting roles. Stress fibre formation and up-regulation of α-smooth muscle actin (αSMA) induced by TGFβ2 could be reversed by Tpm1/2 knock-down by siRNA. Expression of Tpm1/2 and stress fibre formation induced by TGFβ2 could be reversed by FGF2. Furthermore, FGF2 delivery to TGFβ-treated LECs perturbed EMT by reactivating the mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) pathway and subsequently enhanced EMT. Conversely, MEK inhibitor (PD98059) abated the FGF2-mediated Tpm1/2 and αSMA suppression. However, we found that normal LECs which underwent EMT showed enhanced migration in response to combined TGFβ and FGF2 stimulation. These findings may help clarify the mechanism reprogramming the actin cytoskeleton during morphogenetic EMT cell proliferation and fibre regeneration in PCO. We propose that understanding the physiological link between levels of FGF2, Tpm1/2 expression and TGFβs-driven EMT orchestration may provide clue(s) to develop therapeutic strategies to treat PCO based on Tpm1/2.
authors.affiliation: Department of Ophthalmology, Kanazawa Medical University, Uchinada, Kahoku-gun, Ishikawa, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Kubo
authors.affiliation: Department of Ophthalmology, Kanazawa Medical University, Uchinada, Kahoku-gun, Ishikawa, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Department of Ophthalmology, Kanazawa Medical University, Uchinada, Kahoku-gun, Ishikawa, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Oncogenic Pathology, Kanazawa Medical University, Uchinada, Kahoku-gun, Ishikawa, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Kiyokawa
authors.affiliation: Department of Ophthalmology, Kanazawa Medical University, Uchinada, Kahoku-gun, Ishikawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Dhirendra P
authors.initials: DP
authors.lastname: Singh
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D058442:Capsule Opacification / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D007903:Lens Capsule, Crystalline / Q000187:drug effects / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008807:Mice, Inbred BALB C; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D053781:Transforming Growth Factor beta2 / Q000494:pharmacology*; D014335:Tropomyosin / Q000378:metabolism*
chemical_list: D000199:Actins; D015415:Biomarkers; D034741:RNA, Small Interfering; D053781:Transforming Growth Factor beta2; D014335:Tropomyosin; D016222:Fibroblast Growth Factor 2
keywords: FGF2; TGFβ2; epithelial-mesenchymal transition; lens epithelial cells; tropomyosin