Keratoconus Associated With Corneal Stromal Amyloid Deposition Containing TGFBIp

Tai, Tak Yee Tania; Damani, Mausam R.; Vo, Rosalind C.; Rayner, Sylvia A.; Glasgow, Ben J.; Hofbauer, John; Casey, Richard; Aldave, Anthony J.

doi:10.1097/ico.0b013e31818c9003

Cited by 21 publications

(12 citation statements)

References 24 publications

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“…Previous studies by us1517 and others2542434445 have indicated a link between KC pathophysiology and the TGF-β pathway. In order to determine if Quercetin inhibited terminal myofibroblast differentiation in a TGF-β dependent manner, we investigated changes in the TGF-β pathway.…”

Section: Resultsmentioning

confidence: 90%

Quercetin Attenuates Lactate Production and Extracellular Matrix Secretion in Keratoconus

McKay

Lyon

Sarker-Nag

et al. 2015

Sci Rep

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Keratoconus(KC) is an ecstatic corneal disease leading to corneal-thinning and the formation of a cone-like cornea. Elevated lactate levels, increased oxidative stress, and myofibroblast formation have all been previously reported. In the current study, we assess the role of Quercetin on collagen secretion and myofibroblast formation in KC in vitro. Human corneal fibroblasts(HCFs) and human keratoconus cells(HKCs) were treated with a stable Vitamin C derivative and cultured for 4 weeks, stimulating formation of a self-assembled extracellular matrix. All samples were analyzed using Western blots and targeted tandem mass spectrometry. Our data showed that Quercetin significantly down regulates myofibroblast differentiation and fibrotic markers, such as α-smooth muscle actin (α-SMA) and Collagen III (Col III), in both HCFs and HKCs. Collagen III secretion was reduced 80% in both HCFs and HKCs following Quercetin treatment. Furthermore, Quercetin reduced lactate production by HKCs to normal HCF levels. Quercetin down regulated TGF-βR2 and TGF-β2 expression in HKCs suggesting a significant link to the TGF-β pathway. These results assert that Quercetin is a key regulator of fibrotic markers and ECM assembly by modulating cellular metabolism and TGF-β signaling. Our study suggests that Quercetin is a potential therapeutic for treatment of corneal dystrophies, such as KC.

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Section: Resultsmentioning

confidence: 90%

Quercetin Attenuates Lactate Production and Extracellular Matrix Secretion in Keratoconus

McKay

Lyon

Sarker-Nag

et al. 2015

Sci Rep

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“…Recently, potential mutation in TGFBI was identified in Chinese KC patients (36). TGFBIp has been identified in primary amyloid deposits of hereditary corneal dystrophies and in secondary amyloidosis of the cornea of diverse etiologies (37), as well as in corneal stromal amyloid deposits in KC patients (38). Increased levels of TGFBIp have been identified in corneas of patients with Fuchs’ endothelial corneal dystrophy (39, 40).…”

Section: Discussionmentioning

confidence: 99%

Abnormal Regulation of Extracellular Matrix and Adhesion Molecules in Corneas of Patients with Keratoconus

Bykhovskaya¹,

Gromova²,

Makarenkova³

et al. 2016

International Journal of Keratoconus and Ectatic Corneal Diseases

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Aim To identify changes in the expression of genes coding for extracellular matrix (ECM) proteins in patients with non-inflammatory corneal disorder keratoconus (KC), patients with corneal scarring, and normal controls. Materials and Methods Total RNA extracted from corneal tissue of 13 KC patients, 2 patients with corneal scaring and 4 normal controls was analyzed using Human Extracellular Matrix & Adhesion Molecules Profiler PCR Array. Statistically significant changes in gene expression were identified using the Data Analysis software. Results Comparison of KC and control corneas with thresholds of 1.5 or greater fold change and a p-value of 0.05 or lower, revealed 21 differentially expressed genes, 16 genes were downregulated and 5 were upregulated. Among transcripts downregulated in KC patients we identified THBS1, ADAMTS1, SPP1, several collagens and integrins. We found TGFBI (BIGH3) gene was the most significantly upregulated transcript. Conclusion Development of keratoconus results in deregulation of gene expression of extracellular matrix and adhesion molecules. Clinical Significance Downregulation of collagens and upregulation of TGFBI repeatedly identified in KC patients may be used as clinical markers of the disease.

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“…However, no mutations in the hotspots of the TGFBI gene were found in this case, suggesting that the hyalinosis and amyloidosis were secondary in nature. Secondary amyloidosis has previously been reported in Fuchs endothelial dystrophy8 and a variety of corneal degenerations9, 10, but not in MCD. Taken together, this clinicopathological report is noteworthy as case 1 represents MCD with degenerative hyalinosis and amyloidosis.…”

Section: Discussionmentioning

confidence: 89%

Novel CHST6 Gene Mutations in 2 Unrelated Cases of Macular Corneal Dystrophy

Patel

Harocopos

Chang

et al. 2011

Cornea

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Purpose To investigate possible mutations in the carbohydrate sulfotransferase 6 (CHST6) gene of two unrelated cases of macular corneal dystrophy (MCD) and to report atypical stromal deposits in one of them. Methods Corneal tissues were stained with anti-sulfated keratan sulfate (KS), anti-transforming growth factor beta 1-induced protein (TGFBIp), thioflavin-T, alcian blue, and Masson trichrome. Sequencing was performed to identify potential mutations in the CHST6 gene and the fourth and twelfth exons of the TGFBI gene. Results Alcian blue staining revealed the presence of multiple subepithelial and intra-stromal mucopolysaccharide deposits, confirming the diagnosis of MCD in both cases. Immunofluorescence staining in case 1 revealed the presence of sulfated KS only in the keratocytes and select endothelial cells, consistent with MCD type IA. Preferential expression of sulfated KS was observed in keratocytes and extracellular stromal matrix in case 2, consistent with MCD type II. Atypical sub-epithelial and superficial stromal deposits were observed in case 1, which stained positively with alcian blue, eosin, Masson trichrome and thioflavin-T indicating the presence of hyaline and amyloid materials. CHST6 gene sequencing revealed two heterozygous mutations in case 1 (a p.Arg211Gln and a novel mutation of p.Arg177Gly) and a novel homozygous mutation of p.Pro186Arg in case 2. No mutations were found in exons 4 or 12 of the TGFBI gene in case 1. Conclusions Secondary hyalinosis and amyloidosis occur in a case of MCD type IA with a novel p.Arg177Gly mutation in CHST6. A novel p.Pro186Arg mutation in CHST6 is associated with MCD type II in an African American.

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Keratoconus Associated With Corneal Stromal Amyloid Deposition Containing TGFBIp

Cited by 21 publications

References 24 publications

Quercetin Attenuates Lactate Production and Extracellular Matrix Secretion in Keratoconus

Quercetin Attenuates Lactate Production and Extracellular Matrix Secretion in Keratoconus

Abnormal Regulation of Extracellular Matrix and Adhesion Molecules in Corneas of Patients with Keratoconus

Novel CHST6 Gene Mutations in 2 Unrelated Cases of Macular Corneal Dystrophy

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