2. Academic Validation
  3. TGFβ1-Induced Fibrotic Responses of Conjunctival Fibroblasts through the Wnt/β-Catenin/CRYAB Signaling Pathway

TGFβ1-Induced Fibrotic Responses of Conjunctival Fibroblasts through the Wnt/β-Catenin/CRYAB Signaling Pathway

  • Am J Pathol. 2024 Jun 13:S0002-9440(24)00201-3. doi: 10.1016/j.ajpath.2024.05.002.
Xiaohui Wang 1,  Kaiping Chen 2,  Yihua Yao 1,  Yijun Lin 1,  Juhua Yang 3,  Yihua Zhu 4,  Biting Zhou 5
Affiliations

Affiliations

  • 1 Department of Ophthalmology, First Affiliated Hospital, Fuzhou, China; Department of Ophthalmology, National Regional Medical Center, First Affiliated Hospital-Binhai District, Fujian Medical University, Fuzhou, China; Fujian Institute of Ophthalmology, First Affiliated Hospital, Fuzhou, China; Fujian Provincial Clinical Medical Research Center of Eye Diseases and Optometry, First Affiliated Hospital, Fuzhou, China.
  • 2 Department of Ophthalmology, First Affiliated Hospital, Fuzhou, China.
  • 3 Department of Bioengineering and Biopharmaceutics, School of Pharmacy, First Affiliated Hospital, Fuzhou, China.
  • 4 Department of Ophthalmology, First Affiliated Hospital, Fuzhou, China; Department of Ophthalmology, National Regional Medical Center, First Affiliated Hospital-Binhai District, Fujian Medical University, Fuzhou, China; Fujian Institute of Ophthalmology, First Affiliated Hospital, Fuzhou, China; Fujian Provincial Clinical Medical Research Center of Eye Diseases and Optometry, First Affiliated Hospital, Fuzhou, China. Electronic address: zhuyihua209@163.com.
  • 5 Department of Ophthalmology, First Affiliated Hospital, Fuzhou, China; Department of Ophthalmology, National Regional Medical Center, First Affiliated Hospital-Binhai District, Fujian Medical University, Fuzhou, China; Fujian Institute of Ophthalmology, First Affiliated Hospital, Fuzhou, China; Fujian Provincial Clinical Medical Research Center of Eye Diseases and Optometry, First Affiliated Hospital, Fuzhou, China. Electronic address: zhoubiting@126.com.
PMID: 38879081 DOI: 10.1016/j.ajpath.2024.05.002
Abstract

Conjunctival fibrosis is a common postoperative complication of glaucoma filtration surgery, resulting in uncontrolled intraocular pressure and surgery failure. Therefore, it is urgent to understand the molecular mechanisms underlying conjunctival fibrosis and to explore novel pharmacologic anti-fibrosis therapies for glaucoma filtration surgery. The 4D-DIA quantitative proteomic results, coupled with experimental data, revealed the activation of the Wnt/β-catenin pathway in transforming growth factor (TGF)-β1-induced human conjunctival fibroblasts (HConFs). Treatment with ICG-001, a Wnt/β-catenin Inhibitor, effectively inhibited cell proliferation and migration in TGFβ1-treated HConFs. ICG-001 treatment alleviated the increased generation of extracellular matrix proteins induced by TGFβ1. In addition, ICG-001 reduced the expression level of α smooth muscle actin (α-SMA) and inhibited cell contractility in TGFβ1-treated HConFs. Proteomics data further suggested that αB-crystallin (CRYAB) was a downstream target of Wnt/β-catenin, which was up-regulated by TGFβ1 and down-regulated by ICG-001. Immunoblotting assay also indicated that ICG-001 reduced the expressions of ubiquitin and β-catenin in TGFβ1-treated HConFs, implying that CRYAB stabilized β-catenin by inhibiting its ubiquitination degradation. Exogenous CRYAB promoted cell viability, increased extracellular matrix protein levels, and up-regulated α-SMA expression of HConFs under TGFβ1 stimulation. CRYAB rescued TGFβ1-induced fibrotic responses that were suppressed by ICG-001. In conclusion, this study elucidates the regulatory mechanism of the Wnt/β-catenin/CRYAB pathway in conjunctival fibrosis, offering promising therapeutic targets for mitigating bleb scarring after glaucoma filtration surgery.

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