ITF2357 transactivates Id3 and regulate TGFβ/BMP7 signaling pathways to attenuate corneal fibrosis. Sci Rep 2016 Feb 11;6:20841
Date
02/13/2016Pubmed ID
26865052Pubmed Central ID
PMC4750002DOI
10.1038/srep20841Scopus ID
2-s2.0-84958581269 (requires institutional sign-in at Scopus site) 36 CitationsAbstract
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 TGFβ signaling pathway. In this study, we investigated safety, efficacy and mechanism of action of a HDACi, ITF2357 in TGFβ-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 αVβ3 expression with a reduction in corneal haze. In addition, ITF2357 reduced myofibroblast formation, suppressed phosphorylation of Smad proteins in TGFβ 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 TGFβ-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 TGFβ/BMP7 signaling pathways.
Author List
Lim RR, Tan A, Liu YC, Barathi VA, Mohan RR, Mehta JS, Chaurasia SSAuthor
Shyam S. Chaurasia PhD Associate Professor in the Ophthalmology and Visual Sciences department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBone 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