Citation:Chung JK,Park SA,Hwang HS,Kim KS,Cho YJ,You YS,Kim YS,Jang JW,Lee SJ.Effects of exogenous recombinant human bone morphogenic protein-7 on the corneal epithelial mesenchymal transition and fibrosis.Int J Ophthalmol 2017;10(3):329-335,doi:10.18240/ijo.2017.03.01
Effects of exogenous recombinant human bone morphogenic protein-7 on the corneal epithelial mesenchymal transition and fibrosis
Received:June 07, 2016  Revised:November 18, 2016
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DOI:10.18240/ijo.2017.03.01
Key Words:bone morphogenic protein-7; corneal fibrosis; epithelial mesenchymal transition; myodifferentiation; transforming growth factor-β
Fund Project:Supported by the Soonchunhyang University Research Fund, the WPM project, Ministry of trade, industry & energy (No.10037842); the National Research Foundation of Korea (No.NRF-2016R1C1B2015622); Recombinant human BMP-7 protein was kindly provided by Cellumed Co., Ltd.
                          
AuthorInstitution
Jin Kwon Chung Department of Ophthalmology, Soonchunhyang University College of Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea.
Shin Ae Park Eyegene Inc., Seoul 07528, Korea
Hee Sun Hwang Eyegene Inc., Seoul 07528, Korea
Kwang Sung Kim Eyegene Inc., Seoul 07528, Korea
Yang Je Cho Eyegene Inc., Seoul 07528, Korea
Yong Sung You Nune Eye Hospital, Seoul 06198, Korea
Young Sik Kim Cellumed. Co., Ltd., Seoul 08501, Korea
Ju Woong Jang Cellumed. Co., Ltd., Seoul 08501, Korea
Sung Jin Lee Department of Ophthalmology, Soonchunhyang University College of Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea.
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Abstract:
      AIM: To evaluate the effect of exogenous recombinant human bone morphogenic protein-7 (rhBMP-7) on transforming growth factor-β (TGF-β)-induced epithelial mesenchymal cell transition (EMT) and assessed its antifibrotic effect via topical application.

    METHODS: The cytotoxic effect of rhBMP-7 was evaluated and the EMT of human corneal epithelial cells (HECEs) was induced by TGF-β. HECEs were then cultured in the presence of rhBMP-7 and/or hyaluronic acid (HA). EMT markers, fibronectin, E-cadherin, α-smooth muscle actin (α-SMA), and matrix metaloproteinase-9 (MMP-9), were evaluated. The level of corneal fibrosis and the reepithelization rate were evaluated using a rabbit keratectomy model. Expression of α-SMA in keratocytes were quantified following treatment with different concentrations of rhBMP-7.

    RESULTS: Treatment with rhBMP-7 attenuated TGF-β-induced EMT in HECEs. It significantly attenuated fibronectin secretion (31.6%; P<0.05), the α-SMA protein level (72.2%; P<0.01), and MMP-9 expression (23.6%, P<0.05) in HECEs compared with cells grown in the presence of TGF-β alone. E-cadherin expression was significantly enhanced (289.7%; P<0.01) in the presence of rhBMP-7. Topical application of rhBMP-7 combined with 0.1% HA significantly reduced the amount of α-SMA+ cells by 43.18% (P<0.05) at a concentration of 2.5 ?g/mL and by 47.73% (P<0.05) at 25 ?g/mL, compared with the control group, without disturbing corneal reepithelization.

    CONCLUSION: rhBMP-7 attenuates TGF-β-induced EMT in vitro, and topical application of rhBMP-7 reduces keratocyte myodifferentiation during the early wound healing stages in vivo without hindering reepithelization. Topical rhBMP-7 application as biological eye drops seems to be feasible in diseases involving TGF-β-related corneal fibrosis with corneal reepithelization disorders.

PMC FullText Html:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360764/
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