Please use this identifier to cite or link to this item: https://doi.org/10.1038/srep20841
Title: ITF2357 transactivates Id3 and regulate TGF?/BMP7 signaling pathways to attenuate corneal fibrosis
Authors: Lim, R.R
Tan, A
Liu, Y.-C 
Barathi, V.A 
Mohan, R.R
Mehta, J.S 
Chaurasia, S.S
Keywords: collagen type 1
collagen type 4
fibronectin
givinostat hydrochloride
histone deacetylase inhibitor
hydroxamic acid
inhibitor of differentiation protein
osteogenic protein 1
procollagen proline 2 oxoglutarate 4 dioxygenase
Smad protein
transforming growth factor beta
vitronectin receptor
adverse effects
animal
antagonists and inhibitors
cornea stroma
disease model
drug effects
fibroblast
fibrosis
gene expression regulation
genetics
human
metabolism
pathology
phosphorylation
photorefractive keratectomy
primary cell culture
rabbits and hares
signal transduction
Animals
Bone Morphogenetic Protein 7
Collagen Type I
Collagen Type IV
Corneal Stroma
Disease Models, Animal
Fibroblasts
Fibronectins
Fibrosis
Gene Expression Regulation
Histone Deacetylase Inhibitors
Humans
Hydroxamic Acids
Inhibitor of Differentiation Proteins
Integrin alphaVbeta3
Phosphorylation
Photorefractive Keratectomy
Primary Cell Culture
Procollagen-Proline Dioxygenase
Rabbits
Signal Transduction
Smad Proteins
Transforming Growth Factor beta
Issue Date: 2016
Publisher: Nature Publishing Group
Citation: Lim, R.R, Tan, A, Liu, Y.-C, Barathi, V.A, Mohan, R.R, Mehta, J.S, Chaurasia, S.S (2016). ITF2357 transactivates Id3 and regulate TGF?/BMP7 signaling pathways to attenuate corneal fibrosis. Scientific Reports 6 : 20841. ScholarBank@NUS Repository. https://doi.org/10.1038/srep20841
Rights: Attribution 4.0 International
Abstract: Corneal fibrosis is often seen in patients with ocular trauma and infection that compromises corneal transparency resulting in vision loss. Treatment strategies including NSAIDs, steroids, MMC and corneal transplants have shown tremendous success but with several side effects and cellular toxicity. Histone deacetylase inhibitors (HDACi) have been shown to inhibit corneal fibrosis via TGF? signaling pathway. In this study, we investigated safety, efficacy and mechanism of action of a HDACi, ITF2357 in TGF?-stimulated in vitro primary human cornea stromal fibroblasts (pHCSFs) and in vivo in a photorefractive keratectomy-treated rabbit model of corneal fibrosis. We found that in vivo ITF2357 decreased collagen I, collagen IV, fibronectin, integrin ?V?3 expression with a reduction in corneal haze. In addition, ITF2357 reduced myofibroblast formation, suppressed phosphorylation of Smad proteins in TGF? pathway and inhibited key responsive protein, P4HA1 involved in pro-collagen synthesis. Treatment of pHCSFs with ITF2357 activated BMP7 levels and expressed all the members of inhibitor of differentiation proteins (Id1-Id4), however, it failed to rescue TGF?-driven transdifferentiation of fibroblasts to myofibroblasts in the presence of siRNA specific to Id3. We conclude that ITF2357 is a potential anti-fibrotic drug that exerts its action via activation of Id3, a downstream target of TGF?/BMP7 signaling pathways.
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/182505
ISSN: 2045-2322
DOI: 10.1038/srep20841
Rights: Attribution 4.0 International
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