Matrix metalloproteinases and their inhibitors in Fuchs endothelial corneal dystrophy

Xu, Isabelle; Thériault, Marius; Brunette, Isabelle; Rochette, Patrick J.; Proulx, Stéphanie

doi:10.1016/j.exer.2021.108500

Cited by 12 publications

(7 citation statements)

References 65 publications

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“…CECs express multiple MMPs, including MMPs 2, three and 7. MMP 2, three and seven have been shown to cleave either decorin, biglycan or beta-glycan to release TGF-β ( Imai et al, 1997 ; Xu et al, 2021 ). However, in FECD, MMP-2 expression is downregulated and the expression of various MMP inhibitors (TIMPs) are upregulated ( Xu et al, 2021 ).…”

Section: Age-related Diseases In the Eyementioning

confidence: 99%

“…MMP 2, three and seven have been shown to cleave either decorin, biglycan or beta-glycan to release TGF-β ( Imai et al, 1997 ; Xu et al, 2021 ). However, in FECD, MMP-2 expression is downregulated and the expression of various MMP inhibitors (TIMPs) are upregulated ( Xu et al, 2021 ). Consequently, it seems less likely that aberrant MMP activity is contributing significantly to the increased TGF-β signaling in FECD.…”

Section: Age-related Diseases In the Eyementioning

confidence: 99%

“…A major aspect of the pathogenesis of both AMD and FECD is the disorganization of the local extracellular matrix (ECM) and the toxic accumulation of protein deposits (referred to as drusen in AMD and guttae in FECD) on the underlying basement membrane (Bruch’s membrane in AMD and Descemet’s membrane in FECD). These pathogenic mechanisms can be linked to both altered expression patterns of ECM protein components and aberrant protease activity ( Luibl et al, 2006 ; Jurkunas et al, 2009 ; Bhutto and Lutty, 2012 ; Okumura et al, 2015 ; Okumura et al, 2017 ; Ong Tone et al, 2021 ; Xu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Potential role of extracellular granzyme B in wet age-related macular degeneration and fuchs endothelial corneal dystrophy

Dubchak

Obasanmi²,

Zeglinski³

et al. 2022

Front. Pharmacol.

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Age-related ocular diseases are the leading cause of blindness in developed countries and constitute a sizable socioeconomic burden worldwide. Age-related macular degeneration (AMD) and Fuchs endothelial corneal dystrophy (FECD) are some of the most common age-related diseases of the retina and cornea, respectively. AMD is characterized by a breakdown of the retinal pigment epithelial monolayer, which maintains retinal homeostasis, leading to retinal degeneration, while FECD is characterized by degeneration of the corneal endothelial monolayer, which maintains corneal hydration status, leading to corneal edema. Both AMD and FECD pathogenesis are characterized by disorganized local extracellular matrix (ECM) and toxic protein deposits, with both processes linked to aberrant protease activity. Granzyme B (GrB) is a serine protease traditionally known for immune-mediated initiation of apoptosis; however, it is now recognized that GrB is expressed by a variety of immune and non-immune cells and aberrant extracellular localization of GrB substantially contributes to various age-related pathologies through dysregulated cleavage of ECM, tight junction, and adherens junction proteins. Despite growing recognition of GrB involvement in multiple age-related pathologies, its role in AMD and FECD remains poorly understood. This review summarizes the pathophysiology of, and similarities between AMD and FECD, outlines the current knowledge of the role of GrB in AMD and FECD, as well as hypothesizes putative contributions of GrB to AMD and FECD pathogenesis and highlights the therapeutic potential of pharmacologically inhibiting GrB as an adjunctive treatment for AMD and FECD.

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Section: Age-related Diseases In the Eyementioning

confidence: 99%

Section: Age-related Diseases In the Eyementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Potential role of extracellular granzyme B in wet age-related macular degeneration and fuchs endothelial corneal dystrophy

Dubchak

Obasanmi²,

Zeglinski³

et al. 2022

Front. Pharmacol.

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“…Cell morphology was classified according to the average CI: endothelial/hexagonal morphology (CI > 0.68), intermediate morphology (CI = 0.68–0.55), and fibroblastic-like/elongated morphology (CI < 0.55). 14 …”

Section: Methodsmentioning

confidence: 99%

TGF-β–Mediated Modulation of Cell–Cell Interactions in Postconfluent Maturing Corneal Endothelial Cells

Santerre

Ghio

Proulx

2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Transforming growth factor-beta (TGF-β) is known to influence many cell functions. In the corneal endothelium, TGF-β1 exerts contextual effects, promoting endothelial–mesenchymal transition in proliferating cells and enhancing barrier integrity in early confluent maturing cells. Herein, we studied how TGF-β isoforms participate in the formation of corneal endothelial intercellular junctions. Methods Corneal endothelial cells (CECs) were cultured using a two-phase media approach. When CECs reached confluence, the proliferation medium was replaced with maturation medium, which was supplemented or not with TGF-β isoforms. The cell morphology (circularity index), intercellular junction protein expression, trans-endothelial electrical resistance (TEER), and permeability of 7-day postconfluent CECs were assessed. Gene transcription and signaling pathways that were activated following maturation in the presence of TGF-β2 were also studied. The beneficial effect of TGF-β2 on CEC maturation was evaluated using ex vivo corneas mounted on a corneal bioreactor. Results The results showed increases in circularity index, membrane localization of junction-related proteins, and TEER when TGF-β isoforms were individually added during the maturation phase, and TGF-β2 was the most effective isoform. Gene profiling revealed an increase in extracellular matrix-related gene expression. In ex vivo cell adhesion experiments, CECs that were matured in the presence of TGF-β2 had a higher circularity index and cell density and exhibited cell membrane-localized junction-related protein expression at earlier time points. Conclusions These results suggest that TGF-β2 can strengthen cell–cell and cell–substrate adhesion, which accelerates barrier integrity establishment and thus enhances CEC functionality.

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“…Under healthy physiological conditions, the activity of MMPs is further regulated by their endogenous inhibitors, known as tissue inhibitors of MMPs (TIMPs). The equilibrium between MMPs and TIMPs is crucial to control their activity [ 44 ].…”

Section: Proteases and Dry Eye Diseasementioning

confidence: 99%

Proteases and Their Potential Role as Biomarkers and Drug Targets in Dry Eye Disease and Ocular Surface Dysfunction

Ramos-Llorca

Scarpellini

Augustyns

2022

IJMS

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Dry eye disease (DED) is a multifactorial disorder that leads to ocular discomfort, visual disturbance, and tear film instability. DED is accompanied by an increase in tear osmolarity and ocular surface inflammation. The diagnosis and treatment of DED still present significant challenges. Therefore, novel biomarkers and treatments are of great interest. Proteases are present in different tissues on the ocular surface. In a healthy eye, proteases are highly regulated. However, dysregulation occurs in various pathologies, including DED. With this review, we provide an overview of the implications of different families of proteases in the development and severity of DED, along with studies involving protease inhibitors as potential therapeutic tools. Even though further research is needed, this review aims to give suggestions for identifying novel biomarkers and developing new protease inhibitors.

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Matrix metalloproteinases and their inhibitors in Fuchs endothelial corneal dystrophy

Cited by 12 publications

References 65 publications

Potential role of extracellular granzyme B in wet age-related macular degeneration and fuchs endothelial corneal dystrophy

Potential role of extracellular granzyme B in wet age-related macular degeneration and fuchs endothelial corneal dystrophy

TGF-β–Mediated Modulation of Cell–Cell Interactions in Postconfluent Maturing Corneal Endothelial Cells

Proteases and Their Potential Role as Biomarkers and Drug Targets in Dry Eye Disease and Ocular Surface Dysfunction

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