Matrix Metalloproteinases and Glaucoma: Comparison
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Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Moo Hyun Kim.

Matrix metalloproteinases (MMPs) are enzymes that decompose extracellular matrix (ECM) proteins. MMPs are thought to play important roles in cellular processes, such as cell proliferation, differentiation, angiogenesis, migration, apoptosis, and host defense. MMPs are distributed in almost all intraocular tissues and are involved in physiological and pathological mechanisms of the eye. MMPs are also associated with glaucoma, a progressive neurodegenerative disease of the eyes. MMP activity affects intraocular pressure control and apoptosis of retinal ganglion cells, which are the pathological mechanisms of glaucoma. It also affects the risk of glaucoma development based on genetic pleomorphism. In addition, MMPs may affect the treatment outcomes of glaucoma, including the success rate of surgical treatment and side effects on the ocular surface due to glaucoma medications. Glaucoma is a neurodegenerative disorder affected by multiple factors, from which more than 60 million patients worldwide suffer. It is characterized by irreversible progressive loss of retinal ganglion cells (RGC) and distinct optic nerve head (ONH) deterioration, which is related to corresponding visual field loss.

  • glaucoma
  • matrix metalloproteinases
  • trabecular meshwork

1. Introduction

Matrix metalloproteinases (MMPs) are proteolytic enzymes characterized by zinc ions at the catalytic site and cysteine switches in the propeptide region. They are secreted as a latent proenzyme that must be activated before it functions via other intra- or extracellular enzymes [1,2][1][2]. After activation, MMPs cleave a wide range of extracellular matrix (ECM) structures (collagen, gelatin, proteoglycans, laminin, and fibronectin) in the extracellular environment. In addition to ECM structural remodeling, MMPs are also involved in the regulation of cellular functions. They regulate several cell surface receptors and growth factors, chemokines, cytokines, and cell-to-cell adhesion molecules [3,4,5,6][3][4][5][6]. Due to these functions, MMPs are involved in the overall environmental composition of the ECM and thus influence extracellular activities such as apoptosis, cell proliferation, and cell migration [2,3,7,8,9][2][3][7][8][9]. MMP activity is antagonized by TIMPs, α2-macroglobulin, and reversion-inducing cysteine-rich proteins with Kazal motifs. Four groups of TIMPs have been identified that bind MMPs with variable affinities at a 1:1 stoichiometric ratio. In addition to these regulatory factors, post-translational control, cell compartmentalization, and other mechanisms modulate MMP activity [10,11][10][11]. In addition to ECM remodeling, which is the main function of MMPs, MMPs are expressed in various other tissues and cells, suggesting that MMPs affect homeostasis in a wide range of cells and organs. Therefore, when MMP activity is properly controlled, MMPs play an important role in tissue remodeling processes, such as angiogenesis, neural plasticity, organogenesis, and wound healing. However, unregulated MMP activity, such as unbalanced MMP and TIMP activities, can cause many pathological conditions. Metastatic activity in cancer, cardiovascular disorders, neurodegenerative disorders, and many other diseases are related to impaired MMP activity [12,13,14,15,16,17][12][13][14][15][16][17] (Figure 1).
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Figure 1. Effect of matrix metalloproteinases (MMPs) on human pathologic events [12,13,14,15,16,17][12][13][14][15][16][17]. In cancer, metastasis, angiogenesis, and tumor growth are affected by upregulated MMP-7, -8, -10, and -14 activity. Myocardial remodeling and extracellular matrix (ECM) destructions occur in cardiovascular disease by increased MMP-2 and -9 activity. Neuronal injury and disruption of the blood–brain barrier is caused by elevated MMP-1, -2, -3, -7 and -9 activity in neurodegenerative disease. Additionally, in the eye, increased MMP-9 activity affects ocular surface disorder, which can cause dry eye and surface inflammatory change. Furthermore, increased MMP-9 activity can cause retinal ganglion cell death in the retina. Decreased MMP-2 and -9 activity can disrupt homeostasis of intraocular pressure (IOP) in trabecular meshwork.
MMPs can be subdivided according to their sequence similarity, domain organization, and proteolytic activity. Collagenase groups (MMP-1, -8, and -13) can specifically cleave collagen with gelatinases in a synergistic manner. The gelatinase group (MMP-2 and -9) plays many roles by degrading collagens, elastin, and aggrecan and regulating cell signal activity by controlling cytokines and chemokines. The stromelysin group (MMP-3, -10, and -11) is involved in proteoglycan, laminin, and fibronectin degradation but cannot cleave type I collagen. The matrilysin group (MMP-7 and -26) is involved in fibronectin, elastin, and actin degradation and regulates the activity of many cytokines. The membrane-type group (MMP-14, -15, -16, -17, -24, and -25) activates other MMPs and exhibits proteolytic activity against several ECM components. Finally, other groups of MMPs are cell- or tissue-specific enzymes that are not routinely synthesized under specific conditions [18,19][18][19] (Table 1).
Table 1.
 Matrix metalloproteinase (MMP) subtypes and substrates.
MMP Subtypes MMP Number Substrates
Collagenases [20,21,22][20][21][22] MMP-1 type I, II, III, VI, and X collagens; aggrecan; and

entactin
MMP-8 type I, II, and III collagens and aggrecan
MMP-13 type I, II, and III collagens
Gelatinases [20,23,24][20][23][24] MMP-2 type I, IV, V, VII, X, and XI collagens; vitronectin; fibronectin; aggrecan; laminin; elastin; and tenascin C
MMP-9 type IV, V, and XIV collagens; entactin; vitronectin; aggrecan; and elastin
Stormelysins [20,25,26][20][25][26] MMP-3 type III, IV, IX, and X collagens; aggrecan; fibronectin; laminin; tenascin C; and vitronectin
MMP-10 type IV collagen; aggrecan; and fibronectin
MMP-11 type IV collagen; fibronectin; laminin; and aggrecan
Membrane-type MMPs [20,27][20][27] MMP-14 Activator of pro-MMP-2; type I, II, and III collagens; vitronectin; fibronectin; and laminin-1
MMP-15 Activator of pro-MMP-2; tenascin; fibronectin; and aggrecan
MMP-16 Activator of pro-MMP-2; fibronectin;

and type III collagen
MMP-17 Fibrin and cleaves pro-TNF-α
MMP-24 Activator of pro-MMP-2
MMP-25 type IV collagen; gelatin; fibronectin; and fibrin
Metalloelastases [20,26,28][20][26][28] MMP-12 type IV collagen; elastin; proteoglycan;

fibronectin; laminin; and vitronectin
MMP-19 cartilage oligomeric matrix protein and aggrecan
MMP-20 enamel matrix proteins
MMP-28 cartilage oligomeric matrix protein and aggrecan
Other MMPs [20,26,29][20][26][29] MMP-7 aggrecan; fibronectin; laminin; and type IV collagen
MMP-26 fibronectin; type IV collagen; fibrinogen; and gelatin
Glaucoma is a neurodegenerative disorder affected by multiple factors, from which more than 60 million patients worldwide suffer [30]. It is characterized by irreversible progressive loss of retinal ganglion cells (RGC) and distinct optic nerve head (ONH) deterioration, which is related to corresponding visual field loss [31,32,33][31][32][33]. The prevalence of glaucoma increases with age, and elevated intraocular pressure (IOP) is the most important factor in its development and progression. Therefore, lowering the IOP is the most important clinical treatment. However, there are factors that affect glaucoma that cannot be explained by IOP alone, because glaucoma progresses even when intraocular pressure is well controlled [34,35][34][35]. Despite the efforts of many researchers, the exact mechanism by which elevated IOP and multiple other factors affect glaucoma and cause RGC apoptosis and progression at the molecular or cellular levels is little understood. Although some animal clinical studies have shown results that can partially explain the mechanisms underlying the pathogenesis of glaucoma, they often show conflicting results owing to various limitations [36,37,38,39][36][37][38][39].
Despite the unknown effects of various environmental factors, MMPs are important because of their possible association with the etiology of glaucoma, glaucoma type, glaucoma surgery outcomes, and other eye diseases. In this researcontext, weh, researchers reviewed the association between MMPs and glaucoma [30,40,41,42,43,44][30][40][41][42][43][44].

2. Pathogenesis of Glaucoma concerning Matrix Metalloproteinases

2.1. Pathogenesis of Glaucoma Subtypes

Primary angle-closure glaucoma (PACG) is caused by compromised aqueous humor (AH) outflow and anterior chamber angle (ACA) obstruction. In most cases, the PACG angle narrows because of the relative pupillary block, which is related to displacement of the peripheral iris against the trabecular meshwork (TM) [45]. PACG prevalence differs according to ethnicity, sex, and family history. Studies have reported that PACG occurs three times more frequently in Asian populations than in European populations [46[46][47],47], and females are more prone to develop PACG [48,49][48][49]. Studies involving Chinese and Eskimos have shown that individuals with any first-degree relative with PACG are more susceptible to developing PACG [50,51][50][51]. Pseudoexfoliation glaucoma (XFG), which is caused by pseudoexfoliation syndrome (XFS), is the most commonly identifiable cause of open-angle glaucoma and is caused by pseudoexfoliation syndrome (XFS) [52]. XFS is an age-related syndrome characterized by the deposition of white scale-like substances in ocular tissues [53]. Scale-like substances are called exfoliation materials (XFM) and produce an abnormal accumulation of fibrillary elastic ECM [54]. The pathological events of XFG have not been fully confirmed; however, it is assumed that IOP is increased by AH outflow obstruction, which is induced by the deposition of XFM in the TM structure, finally leading to glaucomatous changes in the ONH [54]. Studies involving twins and first-degree relatives with XFS and loss of heterozygosity have indicated that XFG and XFS exhibit strong familial inheritance [55,56,57,58][55][56][57][58]. Juvenile open-angle glaucoma (JOAG) is an uncommon type of primary open-angle glaucoma (POAG), with a high prevalence in individuals aged 5–35 years. Individuals with JOAG follow autosomal dominant inheritance and have a strong family history of POAG [59]. Myocilin gene (MYOC) mutations account for approximately 10% of JOAG cases [31,60][31][60]. It has been suggested that MYOC mutations disrupt MMP and TIMP activities in the TM, causing pathological changes in the development of glaucoma [61,62][61][62].

2.2. Matrix Metalloproteinases and Trabecular Meshwork with Glaucoma

Elevated IOP is one of the main risk factors for glaucoma [34,35][34][35]. IOP is defined as the difference between the production of aqueous humor (AH) in the ciliary body and AH drainage, mainly in trabecular meshwork (TM) and minorly in the uveoscleral pathway [63,64][63][64] (Figure 32). The TM generates the main outflow resistance for the AH, which is positioned at the iridocorneal angle, and its ECM is constantly remodeled by MMPs. ECM composition is continuously remodeled by selective ECM substrate degradation and production of new ECM substrates, including fibronectin, proteoglycans, collagens, and glycosaminoglycans, by TM cells. MMPs play a role in degrading specific ECM substrates [63,65][63][65]. Along with ECM modification, the geometry of the TM changes to regulate permeability via ciliary muscle contraction and form changes in the TM cells [66,67,68][66][67][68]. Many MMPs (MMP-1, -2, -3, -9, -12, and -14) and their local inhibitor TIMP-2 have been synthesized by TM cells [69,70][69][70]. Increasing MMP activity causes an elevated AH outflow rate, whereas inhibiting MMP activity decreases the AH outflow rate [71]. A recent study using a porcine model showed similar results, indicating that reduced MMP-2 and -9 activity is related to elevated IOP [72]. ECM composition changes can be observed when the AH outflow rate is pushed from equilibrium [73].
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Figure 32. Aqueous humor production and outflow in the eye. Aqueous humor (AH) is produced in the ciliary body. After AH enters the posterior chamber of the eye, it flows through the pupil and enters the anterior chamber of the eye (blue arrows). About 60 to 80% of AH outflows to the trabecular pathway (yellow arrow) and others pass through the uveoscleral pathway (green arrow). Increased matrix metalloproteinase (MMP) activity in the trabecular meshwork elevates AH outflow, which in turn reduces intraocular pressure (IOP). However, decreased MMP activity in the trabecular meshwork decreases AH outflow, which causes elevated IOP [63,65,71,72,73][63][65][71][72][73].
When the outflow of AH decreases, IOP increases, which causes mechanical stretching of the TM, owing to pressure changes. This structural change is sensed by TM cells, which trigger homeostatic activity to reduce the IOP. TM cells increased the synthesis of MMPs (MMP-2, -3, and -14) and decreased TIMP-2 production. Altered MMP and TIMP activity causes an increased ECM turnover rate with degraded ECM substrate uptake, changing ECM biosynthesis and changing the ECM environment to adjust outflow resistance. After ECM remodeling, the AH outflow rate increased and returned to normal IOP. In in vitro studies, adding recombinant MMPs to human TM organ cultures induced an elevated AH outflow rate; however, inhibiting MMP activity decreased the outflow rate [66,71,74,75,76,77,78][66][71][74][75][76][77][78]. This suggests that mechanical changes in the TM function as sensors of IOP change. ECM remodeling does not occur by simply releasing endogenous MMPs into the extracellular regions. Aga et al. [79] discovered the detailed regulatory areas. This region, called the podosome- or invadopodia-like structure (PILS), is localized in distinct TM cell areas. Increased MMP-2 and -14 expression has been observed in PILS, and these structures function in cell attachment and ECM turnover in a highly controlled manner. PILSs play an important role because uncontrolled ECM remodeling in the main AH outflow route may disrupt ECM structures, causing dysregulation of outflow resistance. Specifically, in an in vitro study on animal cell cultures, this change in MMP protein levels was not related to changes in mRNA transcription. This suggests that TM cells sense mechanical stretching through interactions between integrin and ECM, which induces signal transduction through signal transduction inhibitors (rapamycin and wortmannin). Finally, ribosomes are recruited to the mRNA to translate MMP-2 and -14 [40,74][40][74]. Disruption of MMP activity has been reported in glaucoma patients. Microscopic TM findings in patients with primary open-angle glaucoma (POAG) show a significant depletion of hyaluronic acid (HA) compared with those without the disease. Normally, MMP-2 and -9 mRNA activity increases HA concentration. Therefore, in patients with POAG, it can be assumed that HA depletion is a result of reduced MMP activity and causes disruption of ECM remodeling, leading to decreased AH outflow rates [80,81][80][81]. Unlike the decreased activity of MMPs in TM, other studies have suggested that increased MMP and TIMP activities are observed in the AH of patients with POAG [82,83][82][83]. Corticosteroids are currently used to treat various ophthalmic diseases [84]. In most cases, when used with caution, there are few side effects, but some patients develop steroid-induced glaucoma [85]. In an in vitro study of human TM cells, dexamethasone decreased MMP-2 and -9 activity compared with the non-dexamethasone control [86]. Another study using human fibroblasts reported similar results [87]. Reduced expression of MMP-2 and -9, which are caused by corticosteroids, may decrease AH outflow and increase IOP, resulting in steroid-induced glaucoma.

2.3. Matrix Metalloproteinases and Neuroretina with Glaucoma

MMPs play a major role in regulating AH outflow resistance by remodeling the ECM in the TM. However, MMPs are also factors that contribute to degenerative conditions in the posterior segment of the eye in glaucoma. Many MMPs and their inhibitors, TIMPs, are expressed in various neuronal and glial cells of the retina and the optic nerve. This expression may affect glaucomatous retinal and optic nerve degeneration by inducing apoptosis of retinal ganglion cells (RGC) and atrophic changes in the optic nerve [88,89,90,91,92,93][88][89][90][91][92][93]. However, the exact mechanism by which elevated IOP induces retinal degeneration and optic nerve atrophy remains unclear. Approximately 2 million RGC axons merge at a point in the posterior segment of the eye known as the optic nerve head (ONH). RGC axons at the ONH enter the neural canal and penetrate the Bruch’s membrane, choroid, and sclera [94]. As the RGC axon bundle passes through the ONH, a mesh-like structure called the lamina cribrosa (LC) supports the RGC axon bundles as they become the optic nerve [95,96][95][96]. In addition to the structural support of RGC axons, the LC has capillaries and glial cells within its structure that manage the ECM environment and provide nutritional support to RGC axons. As RGC axons forming the optic nerve are primarily supported by the LC, they are the main site within the rigid corneoscleral envelope, which is affected by the mechanical stress induced by increased IOP. Mechanical stress in the LC activates connective tissue remodeling cascades involving glial cells, LC cells, and scleral fibroblasts. Glial cells in the LC increase MMP secretion and modulate ECM structures to resemble glaucomatous environments. When ECM remodeling is complete, compression of RGC axons is relieved, and axoplasmic flow continues, which is affected by mechanical stress in the LC [97,98][97][98]. LC and glial cells are very sensitive to changes in mechanical stress that affect LC because they can sense mechanical stress by integrin receptors that are linked directly to the fibrillar ECM with cytoskeletons [99]. Many studies have investigated MMP and TIMP activities and expression in various glaucomatous animal models and humans with glaucomatous optic nerve changes. These studies suggest a mechanism by which MMPs affect glaucomatous optic nerve degeneration. In glaucomatous optic nerves, increased IOP induces mechanical stress in the LC, which is sensed by LC and glial cells. These cells secrete more cytokines (TGF-b1 and TNF-α) than normal cells do. Increased cytokine activity induces MMP-2 expression and ECM remodeling in the ONH. In addition, glial cells transform into reactive rather than quiescent forms and express MT1-MMP and MMP-1. MMP-1 causes continuous ECM degradation if it is not inhibited by TIMP-1, which is secreted by glial cells and RGC. If degradation continues, the LC cannot support RGC axon survival and may induce ONH excavation [41,91,92,97,98,100][41][91][92][97][98][100]. In patients with POAG and normal tension glaucoma (NTG), MMPs (MMP-1, -2, and -3) were enriched in the ONH [39,91,92][39][91][92] (Figure 43).
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Figure 43. Normal retina and optic nerve head (ONH) (A). Retinal ganglion cell (RGC) axon bundle passes lamina cribrosa (LC) and exits the eye. LC supports the RGC axon bundles as they become the optic nerve. Glaucomatous ONH change (B). Increased intraocular pressure causes mechanical stress in the LC. Due to mechanical stress in LC, cytokine activity is increased, which induces matrix metalloproteinase (MMP) expression and extracellular matrix (ECM) remodeling in the ONH. Additionally, mechanical stress cause apoptosis of RGC by increased MMP-9 activity. The aftermath of glaucomatous ONH changes includes cupping of ONH (yellow arrows), retinal nerve fiber layer thinning by RGC apoptosis (red double arrow), and lamina cribrosa disruption (blue arrows) [31,95,96,97,98][31][95][96][97][98].
Aging is another well-known risk factor for the development and progression of glaucoma in addition to elevated IOP. The composition of LC ECM proteins and collagen changes with age. Owing to these changes, the laminar beam becomes thicker with increased collagen and elastin within the cribriform plates [101,102][101][102]. Thickened laminar beams decrease LC elasticity and impede the diffusion of nutrients to the RGC axons. It is more common for aged ONH patients to suffer damage from elevated IOP or other non-IOP related situations [103,104,105][103][104][105]. Increased collagen and elastin levels have been suggested to be responsible for the decreased MMP activity. However, a study with aged human donor eyes showed that all members of the gelatinase family (MMP-2, -9), which are found in the ECM of Bruch’s membrane, are also observed in the ONH [44]. Their results showed that the level of active MMPs was higher than that of the proenzymes. This indicates that the degradation process leads to the regeneration of the LC under normal conditions with or without aging. However, Hussain et al. have suggested that age-related collagens are insoluble, chemically altered, and difficult to degrade. In addition, aged LCs have more advanced glycation end-products, which are powerful inhibitors of MMPs, making enzymatic breakdown more difficult. MMPs play an important role in the regulation of the ECM of the retina, similar to many other human tissues. The interaction between ECM and MMPs affects RGC survival [39]. Specifically, elevated MMP-9 levels expressed by RGCs or reactive astrocytes induce RGC apoptosis by inducing detachment and promoting laminin proteolysis [39,106][39][106]. Animal models of RGC death show elevated MMP-9 activity, and most MMP-9 knockdown mouse models with optic nerve ligation do not show RGC death [90,107,108,109,110,111,112][90][107][108][109][110][111][112]. However, the role of MMP-2 in animal models of RGC death remains controversial. A few studies [89,90,109,110][89][90][109][110] have reported unchanged MMP-2 activity after RGC death, but others have found that MMP-2 activity increased after excitotoxic injury or post-ischemia-reperfusion [108,113][108][113]. The precise mechanism of MMP and TIMP activities in glaucomatous retinas remains elusive and requires further detailed studies. However, some studies using animal and human cell culture models of glaucoma have provided insights into its activity. These studies suggest that events related to glaucomatous changes in the retina (ischemic insults and increased IOP) cause changes in the cellular signal transduction. Elevated cytokine (IL-1) and retinal glutamate levels stimulate MMP-9 synthesis in RGCs and glial cells. IL-1 also stimulates nitric oxide production, which activates dormant extracellular pro-MMP-9. In the ECM, TGF-β2, a well-known MMP inhibitor, is decreased by an increase in the IOP. Through this process, MMP-9 activity increases in the RGC layer and induces apoptosis of RGCs via many cellular signaling cascades. In contrast, in an ocular hypertension model, TIMP-1 showed increased activity, followed by elevated MMP-9 expression, and inhibited the activity of MMP-9 to prevent apoptosis of RGCs. In addition, RGC apoptosis may be stopped by TIMP-1 activity by inhibiting signals that induce RGC apoptosis in a non-MMP-related manner [39,41,108,109,110,114,115][39][41][108][109][110][114][115].

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