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Julia Wessel, Matthias Zenkel, Ursula Schlotzer-Schrehardt, Bjoern Bachmann, Theofilos Tourtas, Friedrich Kruse; Abnormal extracellular matrix production in corneal endothelial cells from patients with late-onset Fuchs corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4727.
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To gain a better understanding of the molecular pathologic mechanisms underlying abnormal extracellular matrix production (ECM) in Fuchs corneal dystrophy (FCD).
Human corneal endothelial-Descemet membrane specimens were obtained from patients with late-onset FCD during DMEK surgery (n=10). To exclude unspecific findings due to endothelial damage specimens from patients with pseudophakic bullous keratopathy (PBK) were differentially analysed (n=3). Normal age-matched endothelial specimens from donor eyes (n=3) and eyes which had to be enucleated because of posterior uveal malignant melanoma (n=3) were used as controls. Gene expression profiles of FCD and control specimens were compared using the “Human Extracellular Matrix and Adhesion Molecule” PCR array (RT2 Profiler PCR Array, Qiagen). Differentially expressed mRNAs were quantified (n=3) in FCD, control and PBK specimens by specific real-time PCR assays (universal probe library, Roche). Various extracellular matrix proteins were localized in cryosections of corneal specimens from FCD, PBK and control eyes by immunohistochemistry. Informed consent has been obtained from the patients and the study has been approved by the local ethics committee.
PCR array analysis revealed a significant upregulation (up to 20-fold; p<0.01) of collagens (collagen type IV α2, collagen type VI α1), proteoglycans (versican), cell adhesion molecules (integrin αL, integrin α4), glycoproteins (fibronectin1, laminin γ1), TGFBI, clusterin, and matrix metalloproteinases (MMP9, MMP14) in FCD endothelial cells as compared to normal controls. Col8A2 expression was not changed in FCD specimens, consistent with the late-onset type of the disease. Specific real-time PCR assays confirmed the PCR array data and displayed a differing expression pattern in FCD as compared to PBK specimens. Immunohistochemistry revealed increased deposition of TGFBI, clusterin, fibrillin-1, fibronectin, collagen types III, IV, V, VI, XVIII, and versican in Descemet's membrane, particularly in the central parts, of FCD corneas.
Our data provide evidence for the FCD-specific upregulation of several ECM components, further strengthening the concept of FCD as a basement membrane disease. Thus, modification of ECM components might be a therapeutic option in FCD.
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