Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-07-28

AUTHORS

Naoki Okumura, Keisuke Hashimoto, Miu Kitahara, Hirokazu Okuda, Emi Ueda, Kyoko Watanabe, Makiko Nakahara, Takahiko Sato, Shigeru Kinoshita, Theofilos Tourtas, Ursula Schlötzer-Schrehardt, Friedrich Kruse, Noriko Koizumi

ABSTRACT

Fuchs endothelial corneal dystrophy (FECD) is a slowly progressive bilateral disease of corneal endothelium in which accumulation of extracellular matrix (ECM) and loss of corneal endothelial cells (CECs) are phenotypic features. The corneal endothelium maintains corneal transparency by regulating water hydration; consequently, corneal endothelial dysfunction causes serious vision loss. The only therapy for corneal haziness due to corneal endothelial diseases, including FECD, is corneal transplantation using donor corneas, and no pharmaceutical treatment is available. We provide evidence that the expression levels of transforming growth factor-β (TGF-β) isoforms and TGF-β receptors are high in the corneal endothelium of patients with FECD. A cell model based on patients with FECD shows that TGF-β signaling induced a chronic overload of ECM proteins to the endoplasmic reticulum (ER), thereby enhancing the formation of unfolded protein and triggering the intrinsic apoptotic pathway through the unfolded protein response (UPR). We propose that inhibition of TGF-β signaling may represent a novel therapeutic target that suppresses cell loss as well as the accumulation of ECM in FECD. More... »

PAGES

6801

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-017-06924-3

DOI

http://dx.doi.org/10.1038/s41598-017-06924-3

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1090882959

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28754918


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28 schema:description Fuchs endothelial corneal dystrophy (FECD) is a slowly progressive bilateral disease of corneal endothelium in which accumulation of extracellular matrix (ECM) and loss of corneal endothelial cells (CECs) are phenotypic features. The corneal endothelium maintains corneal transparency by regulating water hydration; consequently, corneal endothelial dysfunction causes serious vision loss. The only therapy for corneal haziness due to corneal endothelial diseases, including FECD, is corneal transplantation using donor corneas, and no pharmaceutical treatment is available. We provide evidence that the expression levels of transforming growth factor-β (TGF-β) isoforms and TGF-β receptors are high in the corneal endothelium of patients with FECD. A cell model based on patients with FECD shows that TGF-β signaling induced a chronic overload of ECM proteins to the endoplasmic reticulum (ER), thereby enhancing the formation of unfolded protein and triggering the intrinsic apoptotic pathway through the unfolded protein response (UPR). We propose that inhibition of TGF-β signaling may represent a novel therapeutic target that suppresses cell loss as well as the accumulation of ECM in FECD.
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34 schema:keywords ECM proteins
35 Fuchs endothelial corneal dystrophy
36 accumulation
37 accumulation of ECM
38 activation
39 apoptotic pathway
40 bilateral disease
41 cell death
42 cell loss
43 cell model
44 cells
45 chronic overload
46 cornea
47 corneal dystrophy
48 corneal endothelial cells
49 corneal endothelial disease
50 corneal endothelial dysfunction
51 corneal endothelium
52 corneal haziness
53 corneal transparency
54 corneal transplantation
55 death
56 disease
57 donor corneas
58 dysfunction
59 dystrophy
60 endoplasmic reticulum
61 endothelial cells
62 endothelial corneal dystrophy
63 endothelial disease
64 endothelial dysfunction
65 endothelium
66 evidence
67 expression levels
68 extracellular matrix
69 features
70 formation
71 growth
72 haziness
73 hydration
74 induces cell death
75 inhibition
76 intrinsic apoptotic pathway
77 levels
78 loss
79 matrix
80 model
81 novel therapeutic target
82 only therapy
83 overload
84 pathway
85 patients
86 pharmaceutical treatment
87 phenotypic features
88 progressive bilateral disease
89 protein
90 protein response
91 response
92 reticulum
93 serious vision loss
94 show
95 target
96 therapeutic target
97 therapy
98 transparency
99 transplantation
100 treatment
101 unfolded protein response
102 unfolded proteins
103 vision loss
104 water hydration
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