MMPs in the eye: emerging roles for matrix metalloproteinases in ocular physiology (original) (raw)
Related papers
Roles of matrix metalloproteinases in the cornea: A special focus on macular corneal dystrophy
Medicine in Drug Discovery, 2021
Matrix metalloproteinases (MMPs) are endopeptidases that are responsible for the degradation of several components of the extracellular matrix (ECM) and some non-ECM proteins. MMPs are subdivided into 6 groups according to their structure and substrate specificity: collagenases, gelatinases, membrane-type MMPs, stromelysins, and matrilizines. Collagenases are important proteolytic tools during ECM remodeling, tissue regeneration, and organ development. MMPs, especially collagenases, have important roles in ocular processes such as retinal neurogenesis and corneal wound healing. MMP studies on eye research are limited, but there is growing evidence that MMP physiology is key for the ocular system, especially for the cornea. The cornea is predominantly composed of collagen fibrils, which form uniform lamellar lattices. Collagenase-driven ECM remodeling is essential for the cornea. Macular corneal dystrophy (MCD) is a rare inherited disease and characterized by progressive, insoluble accumulation of irregular substances in the corneal ECM. MCD can cause visual acuity loss up to blindness, and there is currently no treatment available. It has been recently reported that certain collagenases are downregulated in MCD disease progression. Here, we review the roles of MMPs in eye diseases and propose possible treatment strategies for MCD. Contents
Protective effects of matrix metalloproteinase-12 following corneal injury
Journal of Cell Science, 2013
Corneal scarring due to injury is a leading cause of blindness worldwide and results from dysregulated inflammation and angiogenesis during wound healing. Here we demonstrate that the extracellular matrix metalloproteinase MMP12 (macrophage metalloelastase) is an important regulator of these repair processes. Chemical injury resulted in higher expression of the fibrotic markers α-smooth muscle actin and type I collagen, and increased levels of angiogenesis in corneas of MMP12−/− mice compared with corneas of wild-type mice. In vivo, we observed altered immune cell dynamics in MMP12−/− corneas by confocal imaging. We determined that the altered dynamics owed to an altered inflammatory response, with delayed neutrophil infiltration during the first day and excessive macrophage infiltration six days later, mediated by altered expression levels of chemokines CCL2 and CXCL1, respectively. Corneal repair returned to normal upon inhibition of these chemokines. Taken together, these data sh...
Role of matrix metalloproteinases in failure to re-epithelialize after corneal injury
The American journal of pathology, 1996
Delayed re-epithelialization of the cornea after injury usually precedes stromal ukceration. Previous findings using a rat thermal injury model suggested that re-epithelialization is impeded by products of resident corneal cells, which destroy adbesive structures at the basement membrane zone. In this study, we provide additional evidencefor this concept. Failure to re-epithelialize was found to correlate with an increase in the amounts of gelatinolytic matrix metalloproteinases present in the rat cornea. One of these gelatinases, gelatinase B, is synthesized by the resident corneal cells, and inhibition of its synthesis correlated with inhibition of basement membrane dissolution. The matrix metalloproteinases collagenase and stromelysin are also synthesized by resident corneal cells in thermaly injured corneas of rabbits, but the timing of bulk enzyme synthesis correlated more closely with deposition of repair tissue in the stroma than with failure to re-epithelialize. Nevertheless, in human corneas with repair defects, gelatinase B and collagenase are synthesized by cells in the basal layer of the epithelium directly adjacent to the basement membrane, suggesting that both couldparticipate in dissolution ofthis structure. Importantly, treatment of thermally injured corneas with a synthetic inhibitor of matrix metalloproteinases significantly improved basement membrane integrity. These data support the concept that over-expression of matrix metalloproteinases by resident corneal cells impedes re-epithelialization after some types ofcorneal injury. (Am J Pathol 1996, 149:1287-1302 Corneal ulceration is a devastating disorder that can cause blindness. Ulcers manifest as a breakdown of the collagenous stromal tissue, a process that was once thought to be a simple physical dissolution described as corneal melting. A major change in our understanding of stromal ulceration occurred when this process was shown to be associated with the secretion of type collagen-degrading enzymes from living cells.' In organ culture, collagenolytic activity was shown to be produced by superficial sections of ulcerating cornea containing the epithelial layer and a small amount of anterior stroma. However, the observation that neutrophil infiltration is a hallmark of stromal ulceration suggested that these cells (with their accumulated stores of hydrolytic enzymes) might provide the more important source of collagenase. Experiments showing that chemical injuries do not ulcerate in animals that have been made neutropenic have provided support for this hypothesis.2
Matrix metalloproteinases as mediators of primary and secondary cataracts
Expert Review of Ophthalmology, 2007
The matrix metalloproteinases (MMPs) are a family of endopeptidases involved in numerous remodeling and fibrotic disorders. Although MMPs have been shown to play important roles in regenerative and disease processes in many parts of the eye, including the cornea, retina and trabecular meshwork, the role of MMPs in the normal and cataractous lens has only recently been studied. These investigations have shown that multiple MMPs are expressed in the lens and their expression is altered in a number of cataract phenotypes. However, anterior subcapsular cataract and posterior capsular opacification, cataracts of a fibrotic nature, show a particular involvement of MMPs. This review will highlight recent findings that suggest a causative role for MMPs in these fibrotic cataract phenotypes.
Matrix metalloproteinases in disease and repair processes in the anterior segment
Survey of ophthalmology
The pathogenesis of many anterior segment disorders and ocular complications following surgery are secondary to the wound healing response. The extent of clinical damage observed is closely related to the amount of scarring and tissue contraction. Matrix metalloproteinases (MMPs) are a family of enzymes that play a vital role in all stages of the wound healing process. They degrade all extracellular matrix components and also have the ability to synthesize collagen and extracellular matrix members, and are therefore important in the remodeling of a wound. Overexpression of MMPs results in excessive extracellular matrix degradation, leading to tissue destruction and loss of organ function. In the case of the anterior segment, this may mean the loss of visual function. This review focuses on the role MMPs have in the development of various anterior segment disorders. The importance of MMPs in the wound healing response and its potential modulation to manipulate the scarring response is being recognized, and current developments will be described. Surv Ophthalmol 47:239 -256 . © 2002 by Elsevier Science Inc. All rights reserved.) Key words. anterior segment • aqueous humour • ciliary body • conjunctiva • cornea • extracellular matrix • glaucoma • lens • matrix metalloproteinase • trabecular meshwork • uvea • wound healing Surv Ophthalmol 47 (3)
Experimental eye research, 2003
Following a myocardial infarction (MI), the homeostatic balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is disrupted as part of the left ventricle (LV) response to injury. The full complement of responses to MI has been termed LV remodeling and includes changes in LV size, shape and function. The following events encompass the LV response to MI: 1) inflammation and LV wall thinning and dilation, 2) infarct expansion and necrotic myocyte resorption, 3) accumulation of fibroblasts and scar formation, and 4) endothelial cell activation and neovascularization.1 , 2 In this review, we will summarize MMP and TIMP roles during these events, focusing on the spatiotemporal localization and MMP and TIMP effects on cellular and tissue-level responses. We will review MMP and TIMP structure and function, and discuss specific MMP roles during both the acute and chronic phases post-MI, which may provide insight into novel therapeutic targets to limit adverse remodeling in the MI setting.
Functional Activity of Matrix Metalloproteinases 2 and 9 in Tears of Patients With Glaucoma
Investigative ophthalmology & visual science, 2017
To evaluate the differential expression of tear matrix metalloproteinases (MMP) 2 and 9 in of patients with various forms of glaucoma. Tear samples were collected with a Schirmer's strip from 148 eyes of 113 patients (medically naïve patients with primary open-angle [POAG] or angle closure glaucoma [PACG] and those with pseudoexfoliation syndrome [PXF] or glaucoma [PXG]). These were compared to patients undergoing cataract surgery (controls) for this cross-sectional study. Functional activities of tear MMP-9 and MMP-2 were analyzed by gelatin zymography. Tenon's capsules (n = 15) were harvested from the inferior quadrant in those undergoing cataract surgery and protein expression of MMP-9 was analyzed by immunohistochemistry (IHC). Hydrogen peroxide (H2O2) stress-induced effects on in vitro activities of MMP-9 in human trabecular meshwork (HTM) cells were analyzed. The MMP-9 activity in tears was increased significantly in POAG, (n = 27), PACG (n = 24), and PXF (n = 40) eyes...
The Role of Matrix Metalloproteinase in Human Body Pathologies
Age-related macular degeneration (AMD) is the leading cause of significant and irreversible central visual loss as it affects a small area of the retina, called the macula. However, the pathogenesis of still fairly understood. AMD has a multifactorial etiology, and its development might be influenced by body peculiarities, environmental and genetic factors. Risk factors such as age, gender, cigarette smoking, color of iris, nutrition, body mass index, oxidative stress, and genetic factors (complement factor H gene, Apo E gene, matrix metalloproteinases (MMPs) genes and others) increase probability to develop AMD. Here, we discuss about choroidal neovascularization process, where hypoxia, inflammatory process, and proteolytic enzymes play a main role, but mainly we focus on the family of matrix metalloproteinases (MMPs), especially on MMP-2,-3 and-9, and their impact on AMD development. MMPs belong to a family of proteolytic zinccontaining enzymes, and their mechanism under normal physiological conditions is precisely regulated, but when is dysregulated, MMPs become a cause of various diseases, including and AMD. MMPs are capable of degrading most of the extracellular matrix components, which are important in the remodeling during angiogenesis. Angiogenesis is the main pathological process associated with age-related macular degeneration development. Activated endothelial cells release MMPs which by degrading the basilar membrane allows capillaries to grow beneath the retina and retinal layers. Such capillaries often bleed, more liquids are filtered through the walls, and fibrous tissue grows within. Furthermore, swelling of the retina and impaired vision occur. In this book chapter, we focus on AMD prevalence, risk factors, clinics, diagnostics and influence of MMP-2,-3 and-9 on AMD development.
Role of matrix metalloproteinases in recurrent corneal melting
Experimental Eye Research, 2010
The aim of this study was to compare the presence and activity of matrix metalloproteinases (MMPs) 1, 2, 3, 7, 8, 9 and 13 in human melted and cadaverous corneas. Twelve melted corneal specimens from three patients with rheumatoid arthritis, one patient with ocular cicatricial pemphigoid and one patient with melting attributed to spastic entropion and ten control corneal buttons were used. The presence of MMPs was detected using indirect enzyme immunohistochemistry. The active forms of MMP-2 and -9 and MMP-3 and -7 were examined by gelatin and casein zymography, respectively. The concentrations of active MMP-1 and -3 were measured using activity assays. Increased immunostaining intensity for MMP-1 and -9 was seen in the corneal epithelium and the anterior stroma of all, and for MMP-2, -3, -7 and -8 of almost all, melted corneas compared to the negative or slightly positive staining of the controls. The posterior stroma showed the presence of MMP-1, -2, -3 and -9 in almost all and of MMP-7 and -8 in half of all melted specimens. A markedly higher level of active MMP-2 was detected in six and active MMP-9 in all of eleven pathologic specimens compared to control specimens, using gelatin zymography. The proenzymes of MMP-3 and -7 and the MMP-7 intermediate cleavage product were detected only in melted corneas using casein zymography. Significantly increased MMP-1 and -3 activity was also found in the melted corneas using activity assays. The markedly increased immunostaining for MMP-1, -2, -3, -7, -8 and -9 as well as the elevated levels of the active forms of MMP-1, -2, -3 and -9 in melted corneal specimens from patients with various diagnoses suggest that although different stimuli may trigger the pathways that lead to the destruction of the extracellular matrix, these enzymes could play a subsequent role in this process.