The Role of Fibrogenesis and Extracellular Matrix Proteins in the Pathogenesis of Graves’ Ophthalmopathy
Abstract
:1. Introduction
2. Cell Mediators in GO
3. Adipogenesis and ECM of GO
4. Transforming Growth Factor-β1 (TGF-β1)-Induced Myofibroblast Transdifferentiation and ECM in GO
5. Hyaluronan Formation by Orbital Fibroblasts
6. Oxidative Stress and Smoking in the ECM of GO
7. Endoplasmic Reticulum (ER) Stress in the ECM of GO
8. Epigenetics and the Gut Microbiome in the ECM of GO
8.1. Histone Deacetylases (HDACs) and DNA Methylation
8.2. MicroRNA in GO
8.3. Other Non-Coding RNAs in GO
8.4. Gut Microbiome in GO
9. Treatment for Tissue Remodeling in GO
9.1. Biologic Agents
9.2. Potential Therapeutic Target—Antioxidants
9.2.1. Selenium (Se)
9.2.2. Pentoxifylline
9.2.3. Nicotinamide and Allopurinol
9.3. Potential Therapeutic Target—Pirfenidone
9.4. Other Potential Targets
10. Concluding Remarks
Funding
Data Availability Statement
Conflicts of Interest
References
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Therapy, FDA Approved [Reference] | Mechanism | Study Design | Disease Status | Outcome | Adverse Effect |
Teprotumumab [2] | Monoclonal antibody against insulin-like growth factor-1 receptor (IGF-1R) | RCT (n = 41) iv 10 mg/kg initially, followed by 20 mg/kg in 3 weeks for 7 additional infusions | Moderate to severe | Improved QOL and proptosis Improvement (83% vs. 10% p < 0.001) after 24 weeks | (1) Hyperlipidemia (2) Hearing impairment |
Therapeutic agents with RCT [reference] | Mechanism | Study design | Disease Status | Outcome | Adverse effect |
Rituximab [77] | Monoclonal antibody against CD20 | RCT (n = 31) iv 2000 mg or 500 mg control: iv methylprednisolone | Moderate to severe | Better ocular motility and QOL after 24 weeks | (1) Infusion reaction (2) Transient hypotension |
[78] | RCT (n = 13) iv 1000 mg twice in 2 weeks control: placebo | Moderate to severe | No benefit | Infectious bronchitis, conjunctivitis, vasculitis, optic neuropathy, gastrointestinal disorder | |
Selenium [85] | Antioxidant | RCT (n = 54) 200 μg/day for 6 months | Mild | Improved QOL and ocular sign, decreased progression | (−) |
Pentoxifylline [85] | Antioxidant | RCT (n = 48) 1200 mg/day for 6 months | Mild | No benefit | Mild gastrointestinal and skin disorders |
[95] | RCT (n = 9) 1200 mg/day for 6 months | Inactive | QOL and proptosis improvement | Mild gastrointestinal disorder | |
Nicotinamide and Allopurinol [100] | Antioxidant | Nonrandomized comparative study (n = 11) Oral allopurinol (300 mg/day) and nicotinamide (300 mg/day) for 3 months | Mild to moderate | Improved soft tissue inflammation | (−) |
Potential therapeutic agents without RCT [reference] | Mechanism | ||||
Tasquinimod [60] | Inhibitor of histone deacetylases 4 (HDAC4), which decreased the mRNA expression of hyaluronan synthase | ||||
Tocilizumab [79] | Monoclonal interleukin-6 receptor antagonist | ||||
Pirfenidone [102,103,104,105] | (1) Decreased inflammation by attenuation of COX-2, prostaglandin E2 (2) Decreased ECM production | ||||
CD40Apt [106] | Specific binding affinity to CD40 represents a promising inhibitor of the CD40-CD40L signaling | ||||
Potential therapeutic targets [reference] | Mechanism | ||||
Antagonist of peroxisome proliferator-activated receptor γ (PPARγ) [10,11,12] | Inhibition of adipogenesis | ||||
Antagonist of transforming growth factor-β1 (TGF-β1) downstream [22,23,24,25] | Inhibition of TGF-β-Induced myofibroblast transdifferentiation in orbital fibroblasts and ECM production | ||||
Antagonist of thioredoxin domain-containing 5 (TXNDC5) [our study, not published] | Reduction in ER stress and tissue remodeling | ||||
Non-coding RNA [61,62,63,64,65,66,67,68,69,70,71,72] | Decreased levels of mi146a: decreased inflammation, decreased fibrosis in GO Increased levels of mi155: decreased fibrosis in GO others (miR-29, miR-21, MiR-27a, miR-27b, miR-130a, circRNA, LncRNA) |
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Chiu, H.-I.; Wu, S.-B.; Tsai, C.-C. The Role of Fibrogenesis and Extracellular Matrix Proteins in the Pathogenesis of Graves’ Ophthalmopathy. Int. J. Mol. Sci. 2024, 25, 3288. https://doi.org/10.3390/ijms25063288
Chiu H-I, Wu S-B, Tsai C-C. The Role of Fibrogenesis and Extracellular Matrix Proteins in the Pathogenesis of Graves’ Ophthalmopathy. International Journal of Molecular Sciences. 2024; 25(6):3288. https://doi.org/10.3390/ijms25063288
Chicago/Turabian StyleChiu, Hsun-I, Shi-Bei Wu, and Chieh-Chih Tsai. 2024. "The Role of Fibrogenesis and Extracellular Matrix Proteins in the Pathogenesis of Graves’ Ophthalmopathy" International Journal of Molecular Sciences 25, no. 6: 3288. https://doi.org/10.3390/ijms25063288