title: Inhibition of matrix metalloproteinase activity reverses corneal endothelial-mesenchymal transition.
abstract: Ex vivo culture or regeneration of corneal endothelial cells often is subjected to gradual endothelial-mesenchymal transition and loss of function. Here, we found that during ex vivo culture, bovine corneal endothelial cells underwent endothelial-mesenchymal transition and had an up-regulated expression and activity of matrix metalloproteinases. Inhibition of matrix metalloproteinase activity in confluent bovine corneal endothelial cells decreased the level of endothelial-mesenchymal transition regulators: snail and slug. The phosphorylation and degradation of the key Wnt signaling pathway modulator active β-catenin also were accelerated with the broad-spectrum matrix metalloproteinase inhibitor Marimastat, which may result from decreased N-cadherin shedding and increased intact N-cadherin molecules on the cell membrane. Intracameral injection of Marimastat also suppressed basic fibroblast growth factor-induced endothelial-mesenchymal transition in a rat corneal endothelium cryo-injury model and significantly diminished the corneal edema. Our study indicated that inhibition of matrix metalloproteinase activity can reverse endothelial-mesenchymal transition and preserve the function of corneal endothelial cells both during ex vivo culture and in vivo. This may offer a potential therapeutic target in regenerative medicine for the treatment of corneal endothelial dysfunctions.
authors.affiliation: Department of Ophthalmology, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Ho
authors.affiliation: Department of Ophthalmology, National Taiwan University, Taipei, Taiwan.
authors.forename: Jung-Shen
authors.initials: JS
authors.lastname: Chang
authors.affiliation: Department of Ophthalmology, National Taiwan University, Taipei, Taiwan.
authors.forename: Chien-Chia
authors.initials: CC
authors.lastname: Su
authors.affiliation: Department of Ophthalmology, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Chang
authors.affiliation: Department of Ophthalmology, National Taiwan University, Taipei, Taiwan.
authors.forename: Fung-Rong
authors.initials: FR
authors.lastname: Hu
authors.affiliation: Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan; College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: jouts@ntu.edu.tw.
authors.forename: Tzuu-Shuh
authors.initials: TS
authors.lastname: Jou
authors.affiliation: Department of Ophthalmology, National Taiwan University, Taipei, Taiwan; College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: ijong@ms8.hinet.net.
authors.forename: I-Jong
authors.initials: IJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003315:Cornea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004728:Endothelium, Corneal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D015820:Cadherins; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C100342:marimastat; D020782:Matrix Metalloproteinases