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ITF2357 transactivates Id3 and regulate TGFβ/BMP7 signaling pathways to attenuate corneal fibrosis
Rayne R Lim1,2, Alison Tan3,4, Yu-Chi Liu3,5
1Ocular Immunology and Angiogenesis Lab, Department of Veterinary Medicine &Surgery, University of Missouri, Columbia, MO 65211, USA.
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.
Insights
ITF2357, a histone deacetylase inhibitor (HDACi), effectively reduces corneal fibrosis by targeting the TGFβ pathway. This novel drug shows promise in treating vision loss caused by corneal scarring.
Area of Science:
- Ophthalmology
- Cell Biology
- Pharmacology
Background:
- Corneal fibrosis, a leading cause of vision loss, results from trauma or infection.
- Current treatments like steroids and transplants have limitations and side effects.
- Histone deacetylase inhibitors (HDACi) show potential for inhibiting corneal fibrosis via the TGFβ pathway.
Purpose of the Study:
- To investigate the safety, efficacy, and mechanism of action of the HDACi, ITF2357.
- To evaluate ITF2357 in TGFβ-stimulated human corneal fibroblasts and a rabbit model of corneal fibrosis.
Main Methods:
- In vitro study using primary human corneal stromal fibroblasts (pHCSFs) stimulated with TGFβ.
- In vivo study using a rabbit model of corneal fibrosis induced by photorefractive keratectomy.
- Analysis of collagen I, collagen IV, fibronectin, integrin αVβ3, myofibroblast markers, Smad protein phosphorylation, P4HA1, BMP7, and Id proteins (Id1-Id4).
Main Results:
- ITF2357 reduced corneal haze and expression of collagen I, collagen IV, fibronectin, and integrin αVβ3 in vivo.
- ITF2357 suppressed myofibroblast formation and Smad protein phosphorylation in the TGFβ pathway.
- ITF2357 inhibited P4HA1, a key protein in pro-collagen synthesis, and activated BMP7 levels in pHCSFs.
- ITF2357 induced Id1-Id4 expression but did not prevent TGFβ-driven transdifferentiation when Id3 was silenced.
Conclusions:
- ITF2357 demonstrates potential as an anti-fibrotic drug for corneal conditions.
- The drug's mechanism involves the TGFβ/BMP7 signaling pathway and activation of Id3.
- ITF2357 warrants further investigation for treating corneal fibrosis and preventing vision loss.
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