title: ITF2357 transactivates Id3 and regulate TGFβ/BMP7 signaling pathways to attenuate corneal fibrosis.
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 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.
authors: Ocular Immunology and Angiogenesis Lab, Department of Veterinary Medicine &Surgery, University of Missouri, Columbia, MO 65211, USA.|Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA.
authors: Rayne R
authors: RR
authors: Lim
authors: Singapore Eye Research Institute, 20 College Road, 169856, Singapore.|Institute of Molecular and Cellular Biology, A*Star, Biopolis, Singapore.
authors: Alison
authors: A
authors: Tan
authors: Singapore Eye Research Institute, 20 College Road, 169856, Singapore.|Singapore National Eye Centre, 11 Third Hospital Avenue, 168751, Singapore.
authors: Yu-Chi
authors: YC
authors: Liu
authors: Singapore Eye Research Institute, 20 College Road, 169856, Singapore.|Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Graduate Medical School, 8 College Rd, 169857, Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Veluchamy A
authors: VA
authors: Barathi
authors: Ocular Immunology and Angiogenesis Lab, Department of Veterinary Medicine &Surgery, University of Missouri, Columbia, MO 65211, USA.|Harry S. Truman Memorial Veteran Hospital, Columbia, MO 65201, USA.|Mason Eye Institute, University of Missouri, Columbia, MO 65211, USA.
authors: Rajiv R
authors: RR
authors: Mohan
authors: Singapore Eye Research Institute, 20 College Road, 169856, Singapore.|Institute of Molecular and Cellular Biology, A*Star, Biopolis, Singapore.|Singapore National Eye Centre, 11 Third Hospital Avenue, 168751, Singapore.
authors: Jodhbir S
authors: JS
authors: Mehta
authors: Ocular Immunology and Angiogenesis Lab, Department of Veterinary Medicine &Surgery, University of Missouri, Columbia, MO 65211, USA.|Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA.|Singapore Eye Research Institute, 20 College Road, 169856, Singapore.|Institute of Molecular and Cellular Biology, A*Star, Biopolis, Singapore.
authors: Shyam S
authors: SS
authors: Chaurasia
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics* / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D003319:Corneal Stroma / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics* / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018903:Photorefractive Keratectomy / Q000009:adverse effects; D061251:Primary Cell Culture; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D055419:Bone Morphogenetic Protein 7; D024042:Collagen Type I; D024141:Collagen Type IV; D005353:Fibronectins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051796:Inhibitor of Differentiation Proteins; D039302:Integrin alphaVbeta3; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D011393:Procollagen-Proline Dioxygenase; C502418:givinostat hydrochloride