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Review  |   November 2013
MMPs in the Trabecular Meshwork: Promising Targets for Future Glaucoma Therapies?
Author Affiliations & Notes
  • Lies De Groef
    Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, Department of Biology, KU Leuven, Leuven, Belgium
  • Inge Van Hove
    Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, Department of Biology, KU Leuven, Leuven, Belgium
  • Eline Dekeyster
    Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, Department of Biology, KU Leuven, Leuven, Belgium
  • Ingeborg Stalmans
    Laboratory of Ophthalmology, Department of Neurosciences, KU Leuven, Leuven, Belgium
  • Lieve Moons
    Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, Department of Biology, KU Leuven, Leuven, Belgium
  • Correspondence: Lieve Moons, Research Group Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, Department of Biology, KU Leuven, Naamsestraat 61, Box 2464, B-3000 Leuven, Belgium; [email protected]
Investigative Ophthalmology & Visual Science November 2013, Vol.54, 7756-7763. doi:https://doi.org/10.1167/iovs.13-13088
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      Lies De Groef, Inge Van Hove, Eline Dekeyster, Ingeborg Stalmans, Lieve Moons; MMPs in the Trabecular Meshwork: Promising Targets for Future Glaucoma Therapies?. Invest. Ophthalmol. Vis. Sci. 2013;54(12):7756-7763. https://doi.org/10.1167/iovs.13-13088.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Glaucoma is one of the world's most common blinding diseases, affecting more than 60 million people worldwide. Although the disease presents as a neurodegenerative disorder affecting retinal ganglion cell axons in the optic nerve and their somata in the retina, the elicitors of this optic neuropathy are often located outside the neuroretina. Disturbances in aqueous humor outflow, leading to ocular hypertension, are considered to be the major risk factor for the development of glaucoma. Although an amplitude of pharmacological and surgical measures is available to lower IOP in glaucoma patients, these are not always sufficient to halt the disease.

Multiple surveys in glaucoma patients, as well as in vitro studies in anterior segment explant or cell cultures, reported changes in the expression and activity of several matrix metalloproteinases (MMPs) in the aqueous humor and trabecular meshwork, in response to elevated IOP. In this review, we describe MMPs as important modulators of aqueous humor outflow, functioning in a feedback mechanism that continuously remodels the trabecular meshwork extracellular matrix composition in order to maintain a stable outflow resistance and IOP. We review the evidence for the involvement of MMPs in glaucoma disease onset and investigate their potential as therapeutic targets for the development of future glaucoma therapies.

Introduction
Matrix metalloproteinases (MMPs) belong to the metzincin clan of the metalloproteinase superfamily, and share a conserved domain structure, consisting of a zinc (II)-containing catalytic domain combined with an autoinhibitory propeptide. This N-terminal prodomain comprises a cysteine residue that coordinates the zinc ion in the active site, keeping the MMP in an inactive or latent state. On cleavage of the prodomain or disruption of this cystin bond, the active site becomes available, resulting in full MMP activity. Most MMPs also contain a C-terminal hemopexin-like domain, linked to the catalytic domain by a hinge region, and, in case of the gelatinases, a fibronectin II-like domain, which both facilitate protein-protein interactions, such as recognition of substrates and binding of TIMPs (tissue inhibitors of MMPs). As MMPs mostly exert their proteolytic function extracellularly, they contain a signal peptide directing their secretion, whereas the membrane-type MMPs (MT-MMPs) are intracellularly activated in the Golgi complex before their translocation to the cell membrane. 13  
MMPs can be categorized either based on their domain structure 1 or on their substrate repertoire. MMP-1, ‐8, and ‐13, which are able to degrade collagen I, II, and III, are grouped as collagenases; MMP-2 and ‐9 are called gelatinases for their ability to degrade gelatin; the stromelysins MMP-3, ‐10, and ‐11, distinguished from the collagenases by their inability to cleave collagen I, are able to cleave many other extracellular matrix (ECM) constituents, such as fibronectin, gelatin, laminins, and proteoglycans, hence their alias proteoglycanases. Finally, there is a heterogeneous group of MMPs containing matrilysin (MMP-7), metalloelastase (MMP-12), enamelysin (MMP-20), endometase (MMP-26), and epilysin (MMP-28). The MT-MMPs (MMP-14, ‐15, ‐16, ‐17, ‐23, ‐24, and ‐25) are considered a separate class, regardless of their substrate preference. 4  
Given their destructive nature, the activity of MMPs is tightly controlled at several levels. First, several MMP genes contain an inducible promoter region with binding sites for transcription factors responsive to growth factors, cytokines, oncogene products, and so forth. 3,5 In addition, also posttranscriptional and epigenetic mechanisms contribute to a strict control of MMP activity, as do compartmentalization, substrate availability, activation, inhibition, and clearance of the MMPs. 5 Activity of secreted and membrane-bound MMPs is further regulated by endogenous inhibitors. In blood and lymph fluid, α2-macroglobulin is the major MMP inhibitor, leading to irreversible clearance via endocytosis of α2-macroglobulin/MMP complexes. The tissue inhibitors of MMPs (TIMPs), on the other hand, are the main MMP inhibitors in tissues and ensure a local, reversible inhibition of MMPs. Currently, four mammalian TIMPs (TIMP1-4) have been identified that bind in a 1:1 stoichiometric fashion to the catalytic domain of their target MMPs. 1,5  
MMPs, originally discovered for their role in tadpole metamorphosis, 6 have been named after their ability to cleave and remodel the ECM. However, 5 decades later, it has become clear that MMPs have in fact a much broader degradome and are vital players in a variety of processes, both in health and disease. Not only do they cleave ECM components, but also proteinases, growth factors, cytokines, cell surface receptors, cell adhesion molecules, and even DNA repair enzymes and mediators of apoptosis, thereby covering a wide range of functions. 
Glaucoma, a multifactorial neurodegenerative disease, is the second most important cause of blindness, estimated to affect more than 60 million people worldwide. 7 This optic neuropathy is characterized by progressive degeneration of the optic nerve and apoptosis of retinal ganglion cell (RGC) somata, and ultimately leads to irreversible blindness. Glaucoma is classically divided into open-angle glaucoma and angle-closure glaucoma, and open-angle glaucoma can present in a primary or secondary form, the latter being caused by various ocular and systemic diseases. 8  
The most prevalent and important risk factor for developing glaucoma, as well as the sole target for clinical intervention, is elevated intraocular pressure (IOP). First-line treatment consists of topical administration of IOP-lowering medications. In case these are ineffective or not well tolerated, laser trabeculoplasty or filtration surgery (generally trabeculectomy) can be considered. Although many patients benefit from IOP-lowering therapies, these do not always succeed in stopping the gradual worsening of visual function, and some patients continue to lose vision in spite of all current treatments. 9,10  
MMPs in the Trabecular Meshwork and Aqueous Humor
MMPs in the Trabecular Meshwork
As mentioned above, in many cases, the glaucomatous damage to the optic nerve is caused by a pathological IOP elevation. IOP is defined by the rate of aqueous humor production by the ciliary body, and the aqueous humor outflow resistance via the iridocorneal tissues (i.e., trabecular meshwork and Schlemm's canal), and to a minor extent via the uveoscleral pathway. Outflow resistance is generated in the trabecular meshwork, of which the ECM is continuously being remodeled by members of the MMP family. MMP-1, ‐2, ‐3, ‐9, ‐12, and ‐14, as well as their endogenous inhibitor TIMP-2, are constitutively secreted by trabecular meshwork cells 1114 (Table 1). Together, they cleave a broad spectrum of trabecular ECM substrates, thereby disrupting the intricate supermolecular organization of the trabecular ECM and allowing endocytosis and intracellular degradation of these cleavage products by the juxtacanalicular cells 12,15 (Fig. a). 
Table 1
 
Overview of the Available Data on MMP/TIMP Expression in the Trabecular Meshwork
Table 1
 
Overview of the Available Data on MMP/TIMP Expression in the Trabecular Meshwork
Expression Pattern Experimental Set-up Reference(s)
MMP-1 Basal MMP-1 expression in the TM Human and bovine TM cell culture, human TM explant culture, human corneoscleral explant culture 11, 14
MMP-1 expression is decreased in the TM after exposure to corticosteroids Human TM culture 52
MMP-2 Basal MMP-2 expression in the TM Human and bovine TM cell culture, human TM explant culture, human corneoscleral explant culture 11, 14
Punctuate MMP-2 immunostaining pattern over the surface and in the cytoplasm of TM cells Human TM cell culture 15
MMP-2 expression in the TM cells colocalizes to podosome- or invadopodia-like structures Human and porcine TM cell culture, human and porcine anterior segment organ culture 22
MMP-2 activity is increased in the TM within 24–72 hours post mechanical stretching, proportional to the degree of stretching Human, bovine, and porcine TM cell culture 12, 15, 21
MMP-2 activity is decreased in the TM of POAG patients Human TM cell culture (POAG) 26
MMP-3 Basal MMP-3 expression in the TM Human and bovine TM cell culture, human corneoscleral explant culture 11, 14, 15
MMP-3 expression is increased in the TM within 24–72 hours post mechanical stretching Human and bovine TM cell culture 19, 21
No changes in MMP-3 expression on mechanical stretching of the TM Human TM cell culture 15
MMP-3 expression in anterior segment is increased in response to elevated IOP Human perfused anterior segment organ culture 18
MMP-9 Basal MMP-9 expression in the TM Human and bovine TM cell culture, human corneoscleral explant culture 11, 15
No basal MMP-9 expression in the TM Human TM cell culture, human TM explant culture 14
Elevated IOP decreases MMP-9 activity in TM cells Human TM cell culture 23
MMP-9 activity is decreased in the TM of POAG patients Human TM cell culture (POAG) 26
MMP-10 MMP-10 expression in the TM is increased upon mechanical stretching Human TM cell culture 19
MMP-11, MMP-12 Basal MMP-11 and ‐12 expression in the TM Human TM cell culture, human TM explant culture 14
MMP-14 Basal MMP-14 expression in the TM Human TM cell culture, human TM explant culture 14
Punctuate MMP-14 immunostaining pattern over the surface and in the nuclei of TM cells Human TM cell culture 15
MMP-14 expression in TM cells colocalizes to podosome- or invadopodia-like structures Human and porcine TM cell culture, human and porcine anterior segment organ culture 22
MMP-14 expression in the TM is increased within 24-72 hours post mechanical stretching Human and porcine TM cell culture 12
MMP-15, MMP-16, MMP-17, MMP-19, MMP-24 Basal MMP-15, ‐16, ‐17, ‐19, and ‐24 expression in the TM Human TM cell culture, human TM explant culture 14
TIMP-1 Basal TIMP-1 expression in the TM Human and bovine TM cell culture, human TM explant culture, human corneoscleral explant culture 11, 14
TIMP-1 expression levels remain unchanged during 72 hours of mechanical stretching Bovine TM cell culture 21
Elevated IOP increases TIMP-1 expression in TM cells Human TM cell culture 23
TIMP-2 Basal TIMP-2 expression in the TM Human TM cell culture, human TM explant culture 14
Cytoplasmic and somewhat “fibril-associated” TIMP-2 immunostaining pattern in TM cells Human TM cell culture 15
TIMP-2 expression is strongly decreased in the TM within 24–48 hours post mechanical stretching Human TM cell culture 15
TIMP-2 expression remains unchanged during 72 hours of mechanical stretching Bovine TM cell culture 21
TIMP-3, TIMP-4 Basal TIMP-3 and ‐4 expression in the TM Human TM cell culture, human TM explant culture 14
Figure
 
IOP is kept under control by an MMP-based feedback mechanism, regulating outflow resistance of the trabecular meshwork. (a) Homeostatic ECM turnover in the trabecular meshwork is actualized by constitutive expression of MMP-1, ‐2, ‐3, ‐9, ‐12, and ‐14, as well as TIMP-2. (b) Mechanical distortions, provoked by IOP elevations, are sensed by trabecular meshwork cells via ECM-integrin interactions and result in the upregulation of MMP-2, ‐3, and ‐14 secretion, while reducing TIMP-2, via an mTOR-mediated intracellular signaling cascade. Note: Outflow resistance is largely generated in the juxtacanalicular portion of the trabecular meshwork (JCT); however, MMP production and function are not exclusive to the JCT portion of the trabecular meshwork, as is depicted in the drawing, but may also occur on the cells of the corneoscleral portion of the meshwork (CSM). SC, Schlemm's canal.
Figure
 
IOP is kept under control by an MMP-based feedback mechanism, regulating outflow resistance of the trabecular meshwork. (a) Homeostatic ECM turnover in the trabecular meshwork is actualized by constitutive expression of MMP-1, ‐2, ‐3, ‐9, ‐12, and ‐14, as well as TIMP-2. (b) Mechanical distortions, provoked by IOP elevations, are sensed by trabecular meshwork cells via ECM-integrin interactions and result in the upregulation of MMP-2, ‐3, and ‐14 secretion, while reducing TIMP-2, via an mTOR-mediated intracellular signaling cascade. Note: Outflow resistance is largely generated in the juxtacanalicular portion of the trabecular meshwork (JCT); however, MMP production and function are not exclusive to the JCT portion of the trabecular meshwork, as is depicted in the drawing, but may also occur on the cells of the corneoscleral portion of the meshwork (CSM). SC, Schlemm's canal.
Any changes in outflow resistance, sufficient to alter the IOP, cause changes in the degree of stretching of the semiporous structure of the trabecular meshwork. In case of IOP elevation, trabecular meshwork cells will sense increased mechanical stretching forces and respond by upregulating their secretion of MMP-2, ‐3, and ‐14, while reducing TIMP-2. 12,1421 This altered MMP/TIMP balance increases the trabecular ECM turnover rate, reduces the aqueous outflow resistance, and restores normal IOP (Fig. b). All evidence for this IOP homeostasis mechanism was corroborated from in vitro experiments using perfused human anterior segment organ cultures, to which addition of recombinant MMP-2, MMP-3, or MMP-9 resulted in a reversible increase in outflow facility, whereas inhibition of endogenous MMP activity reduced outflow rates. 16 Notably, the changes in MMP-2 and MMP-14 protein levels, observed in porcine trabecular meshwork cultures after mechanical stretch treatment, are not accompanied by changes in their mRNA levels. Therefore, it is assumed that trabecular meshwork cells sense and transduce the mechanical distortion via ECM-integrin interactions and that this signaling cascade intracellularly converges to the protein kinase mTOR (mammalian target of rapamycin) as a central mediator, which subsequently initiates selective translation of MMP-2 and MMP-14 by recruiting ribosomes to the mRNA 12 (Fig. b). In addition, this increased MMP-2 and ‐14 expression localizes to distinct areas on trabecular meshwork cells, the so-called “podosome- or invadopodia-like structures” (PILS), which actualize focal degradation and fragment internalization of the ECM. 22  
Of note, aqueous outflow resistance depends on a complex equilibrium of ECM biosynthesis versus proteolysis, and changes might be the result of qualitative alterations in ECM composition, rather than quantitative differences. Indeed, overexpression of the matricellular protein SPARC (secreted protein, acidic and rich in cysteine) in human anterior segment explant cultures, results in qualitative changes in the ECM of the juxtacanalicular portion of the trabecular meshwork and elevated IOP, that could be linked to a shift in MMP/TIMP balance and a selective decrease in MMP-9 activity. 23 Accordingly, Robertson and West-Mays 24 recently reported an increased IOP in MMP-9–deficient mice, despite the fact that they do not display any overt changes in angle morphology at light microscopic level. 
Ultrastructural examinations of the trabecular meshwork of primary open angle glaucoma (POAG) patients indeed reveal a shift in ECM composition. The trabecular meshwork of POAG eyes contains significantly less or even no hyaluronic acid (HA), as compared to normal trabecular meshwork. 25 This reduction in HA is hypothesized to result in a depletion of MMPs, which leads to an accumulation of ECM in the outflow facilities and increased aqueous humor outflow resistance. Both MMP-2 and MMP-9 mRNA levels were found to be elevated with increasing HA concentrations in an in vitro culture of human trabecular meshwork cells. 26 Thus far, it remains unclear how MMP expression is regulated by HA in POAG eyes; however, the HA-CD44-Ras-MEK1-MAPK signaling pathway is believed to be involved. 26  
Remarkably, laser trabeculoplasty, a commonly used procedure to treat glaucomatous IOP elevations, induces a remodeling of the juxtacanalicular region of the trabecular meshwork, resulting in a decreased outflow resistance and a reduced IOP, lasting for up to 5 years. These architectural changes have been attributed to digestion of the ECM by increased levels of MMPs, among other contributing factors, 27 and although this MMP elevation is not likely to last for more than a few weeks, the resulting long-term reduction in IOP suggests a profound ECM remodeling. 28 Indeed, laser trabeculoplasty applied to perfused human anterior segment organ cultures, induced a several-fold increase in MMP-3 mRNA, protein, and activity levels. Also, the cytokines IL-1 (interleukin 1) and TNF-α (tumor necrosis factor α) were found to be highly upregulated on laser trabeculoplasty and to induce expression of MMP-3, MMP-9, and MMP-12 in cultured trabecular meshwork cells. 13,17,2931 Accordingly, intracameral administration of IL-1α significantly increased the outflow rate in rat eyes, presumably via induction of trabecular MMP expression. 32  
MMPs in the Aqueous Humor
In the anterior segment of the eye, the trabecular meshwork cells are responsible for the secretion of MMPs (Table 1). These MMPs stay close to their site of secretion to digest the ECM of the trabecular meshwork, but can also be carried by the aqueous humor (Table 2). Remarkably, MMPs mainly remain in their latent proform here, and the aqueous humor can thus be considered an endogenous reservoir of latent MMPs, which become activated as they circulate through the iridocorneal tissues. 33  
Table 2
 
Overview of the Available Data on MMP/TIMP Expression in Aqueous Humor
Table 2
 
Overview of the Available Data on MMP/TIMP Expression in Aqueous Humor
Expression Pattern Experimental Set-up Reference(s)
MMP-2 MMP-2 is constitutively expressed in the AH, mainly in its proform Human AH samples 36
MMP-2 expression in the anterior segment is increased in response to elevated IOP Human perfused anterior segment organ culture 20
MMP-2 expression in the AH positively correlates with IOP in PEXG patients Human AH samples 35
The TIMP-2/MMP-2 ratio is increased in the AH of POAG, PEXS and PEXG patients Human AH samples 34, 36
Total MMP-2 expression is increased in the AH of USG, PEXS, PEXG, and POAG (not significant), but not CACG or NTG, relative to cataract, while levels of active MMP-2 are decreased; MMP-2 is increasingly converted to its active form in the AH of USG, whereas in PEXS, PEXG, and POAG, MMP-2 is mainly found in its latent form or bound to complexes with TIMPs Human AH samples 37, 38, 41
Latent MMP-2 expression is increased in the AH of glaucoma samples as compared with normal AH samples, whereas active MMP-2 is increased in the iridocorneal angle tissue Canine AH and iridocorneal angle tissue samples 33
MMP-3 MMP-3 expression in the anterior segment is increased in response to elevated IOP Human perfused anterior segment organ culture 18
Total MMP-3 expression is increased in the AH of PEXS, PEXG, and POAG (not significant), relative to cataract Human AH samples 38
MMP-8 MMP-8 expression is increased in the AH of USG, relative to POAG and cataract; MMP-8 is increasingly converted to its active form in the AH of USG, whereas in POAG and cataract, MMP-8 is mainly found in is latent form Human AH samples 37
MMP-9 MMP-9 expression is increased in the AH of USG, relative to POAG and cataract; MMP-9 is increasingly converted to its active form in the AH of USG, whereas in POAG and cataract, MMP-9 is mainly found in its latent form Human AH samples 37
Latent MMP-9 is increased in the iridocorneal angle tissue of glaucoma samples, as compared with normal samples, and is associated with glaucoma status Canine AH and iridocorneal angle tissue samples 33
MMP-10 MMP-10 expression in the anterior segment is increased in response to elevated IOP Human perfused anterior segment organ culture 20
MMP-13, MMP-14 MMP-13 and ‐14 expression is increased in the AH of USG, relative to POAG and cataract; MMP-13 and ‐14 are increasingly converted to their active form in the AH of USG, whereas in POAG and cataract, MMP-13 and ‐14 are mainly found in their latent form Human AH samples 37
TIMP-1 Total TIMP-1 expression is increased in the AH of PEXS, PEXG, and POAG (not significant), relative to cataract Human AH samples 38
TIMP-2 TIMP-2 expression in the AH negatively correlates with IOP in PEXG patients Human AH samples 35
The TIMP-2/MMP-2 ratio is increased in the AH of PEXG patients Human AH samples 34, 38
TIMP-2 expression is increased in the AH of USG, PEXS, and PEXG patients Human AH samples 36, 38
TIMP-2 expression is elevated in the AH of USG, relative to POAG and cataract Human AH samples 37
Both in POAG and pseudoexfoliation glaucoma (PEXG), imbalances between MMPs and TIMPs, in the aqueous humor are key to the etiology of the disease. Whereas the normal relation of MMPs to TIMPs is 1:1, the MMP/TIMP ratio in PAOG and PEXG patients tilts toward a dominance of TIMPs, promoting inappropriate degradation and continuous accumulation of ECM components in the trabecular meshwork. 3438 An altered proteolytic potential, largely due to reduced levels of active MMP-2 and increased TIMP-2 concentrations, is observed in patients with PEXG and to a lesser extent also in those with POAG. 38 Remarkably, despite a decrease in MMP-2 activity, total protein levels of (biologically inactive) MMP-2 increase in POAG and PEXG eyes, 3538 resulting in an enlarged endogenous reservoir of latent MMP-2. This elevated MMP synthesis might be triggered by the increased deposition of matrix components and is most likely a consequence, rather than a cause, of the pathological matrix remodeling and accumulation. 38 In addition, the increased levels of the transforming growth factor (TGF) subunits TGF-β1 and TGF-β2 in the aqueous humor of PEXG and POAG eyes, respectively, might be responsible for the altered MMP and TIMP transcription in these patients. TGF-β1 and TGF-β2 have been shown to upregulate the expression of TIMPs while downregulating MMP expression, and TGF-β2 also promotes the expression of the ECM crosslinking enzyme tissue transglutaminase. 39,40 These concerted actions prevent the destruction of the newly formed matrix and result in fibrosis of the trabecular meshwork. 36,38 Of note, total protein levels of MMP-2 were also found to be elevated in the aqueous humor of glaucomatous dogs; however, in contrast to the findings in humans, active MMP-2 levels were increased as well. 33 A study by Kee et al., 41 investigating MMP-2 expression in chronic angle closure glaucoma and normal tension glaucoma patients, revealed that MMP-2 activity in the aqueous humor of these patients is similar to cataract patients. Indeed, as these glaucoma variants are not related to alterations of the trabecular meshwork, but rather to occlusion of the outflow channel by the iris and to disturbed blood flow to the optic nerve or optic nerve vulnerability, respectively, no changes in MMP-2 activity are expected in these patients. 
Of all MMP family members, MMP-2 and its endogenous inhibitor TIMP-2 have received the most attention; however, also low amounts of MMP-3, ‐7, ‐9, and ‐12 and TIMP-1 were detected in aqueous humor. Except for TIMP-1 and MMP-3, whose total protein levels are increased in PEXG and POAG samples, no changes could be detected in glaucoma versus cataract patients. 38  
Of note, MMPs are also involved in secondary glaucomas, such as uveitis-related secondary glaucoma (USG), however their role markedly differs from that in POAG and PEXG. Whereas MMPs predominantly exist in their latent form and proteolysis is decreased in POAG and PEXG, the aqueous humor of USG eyes contains multiple, mainly active MMPs. As opposed to PEXG and POAG, the observed increase in MMP-2, ‐8, ‐9, ‐13, and ‐14 activity in USG is related to inflammatory activity. This should not come as a surprise, as uveitis is characterized by the invasion of inflammatory cells into the anterior chamber and leakage through the blood-aqueous barrier, both of which are suggested to have MMPs involved. 37 The important role played by MMPs during inflammatory processes might also be a possible explanation for the results presented by Zhou et al., 42 who reported an increased MMP-2 expression and activity in the aqueous humor of DBA/2J mice. The DBA/2J mouse line has been described as a model for human pigmentary glaucoma, but it is also known that the observed pigment dispersion in the eyes is likely to involve immune dysfunction, resulting in a mild chronic inflammatory response in the aqueous humor. Overall, one should be aware that MMPs, notably MMP-2 and MMP-9, are known to be elevated in conditions associated with intraocular inflammation, and that their upregulation is not only limited to glaucoma. 33,37  
MMPs as Targets for Glaucoma Therapy
Current glaucoma therapies are all directed toward a sustained reduction of IOP. These IOP-lowering strategies have been proven to effectively slow down glaucoma progression; however, in some patients, glaucomatous damage continues to proceed despite IOP lowering. 9,10 Given the incomplete treatment options for this irreversible disease, its increasing prevalence due to the aging world population, and the high societal costs (estimated at $1.0–$2.5 billion annually in the United States 43,44 ), the refinement and development of therapeutic approaches fighting ocular hypertension (baroprotective therapies) should persist. 
As MMPs are known as important modulators of trabecular meshwork architecture, they are promising targets for baroprotective therapies aiming at restoring balanced outflow resistance. Indeed, the successful prevention and reversal of ocular hypertension via MMP-1 viral vector–mediated gene therapy in the trabecular meshwork of sheep with steroid-induced glaucoma, 45,46 endorses the concept of glaucoma treatment with an inducible overexpression of ECM modulator genes, restoring the eye's aqueous humor outflow resistance. Compared with the generally used therapeutics and glaucoma surgeries that modulate the eye's outflow facility, controlled overexpression of MMPs via gene therapy might prove an efficient, long-lasting, and less invasive alternative, by restoring the endogenous balance in trabecular ECM turnover. 
Concluding Remarks and Future Directions
In summary, MMP-1, ‐2, ‐3, ‐9, and ‐14 and TIMP-2 have been described to play a modulatory role in IOP homeostasis in the healthy human eye. MMP expression by trabecular meshwork cells was shown to be upregulated in response to increased IOP, thereby restoring aqueous outflow resistance and counteracting IOP elevations (Fig.). However, adjustment of the MMP/TIMP balance is unable to cope with major IOP elevations and both POAG and PEXG patients exhibit increased total protein levels (i.e., pro- and active) of MMP-2 and MMP-3, yet reduced MMP-2 activity, in their aqueous humor, suggesting that this feedback mechanism is still operational but overwhelmed. 
To better understand the exact involvement of MMPs in the anterior segment of the eye, and to fully understand the functional relevance of their altered expression in glaucoma patients (Tables 1 and 2), mechanistic studies are needed to interpret these expression data. Notably, the observed changes in latent versus active MMPs and MMP versus TIMP levels, indicate that MMPs are involved in a very complex manner and that more in-depth knowledge of MMP biology is needed to fully unravel their functions. Importantly, this research should not only focus on their obvious role as ECM-degrading enzymes, but should also take into account their potential contribution to cell-cell and cell-ECM communication; (in)activation of growth factors, cytokines, and cell adhesion molecules; and their influence on various signaling cascades influencing mobility, proliferation, survival, and so forth. One of the major shortcomings today is the lack of data about MMP expression in the anterior segment of the eye in animal models of glaucoma (except for the study of Weinstein et al. in glaucomatous dogs 33 ). By consequence, a first requisite for the disentanglement of the role of MMPs in IOP homeostasis would be to assess whether MMP expression patterns in animal models of glaucoma correspond with what has been observed in humans. 
The MMP-1 viral vector–mediated gene therapy in sheep with ocular hypertension 45,46 is a convincing proof of principle of the high potential of MMP gene therapy to restore trabecular meshwork ECM architecture. The success of AAV2 viral vector–mediated gene therapy to replace the mutated RPE65 gene and to improve vision in patients with Leber's congenital amaurosis, 47,48 as well as the more than 20 clinical trials using viral vector–mediated gene therapy to treat ocular diseases that are currently ongoing, 49 indicate that this approach could be taken to the clinic within a reasonable time frame. Moreover, as evidence points out that ocular hypertension could be treated by increasing MMP activity, MMP balance in the trabecular meshwork could also be modulated via MMP-activating drugs (e.g., tissue plasminogen activator and plasmin), which both have already been approved for other indications in the eye. 50,51  
There is still a long way to go before we will be able to fully appreciate the exact functions of MMPs, yet it is beyond doubt that they are key modulators of IOP homeostasis. The next decade of MMP research is expected to give rise to a new generation of highly specific MMP inhibitors and to alternative therapeutic approaches targeting upstream or downstream factors of MMP-modulated networks. The expression data reviewed here indicate that these novel insights in MMP/TIMP biology might precede a new era of baroprotective therapies that, instead of pharmacologically or surgically interfering with aqueous humor dynamics, restore the intrinsic capability of the trabecular meshwork to remodel its ECM architecture and modulate its aqueous humor outflow resistance. 
Acknowledgments
The authors acknowledge the Research Foundation Flanders and the KU Leuven Research Council. Lies De Groef is a research fellow of the Flemish government agency for Innovation by Science and Technology (IWT-Vlaanderen, Belgium), Eline Dekeyster is a research fellow and Ingeborg Stalmans is a senior clinical research fellow of FWO-Vlaanderen. 
Supported by Research Foundation Flanders (FWO-Vlaanderen, Belgium, G.05311.10), KU Leuven Research Council (KU Leuven, Belgium, BOF-OT/10/033), and Flemish government agency for Innovation by Science and Technology. The funding organizations had no role in the design or conduct of this research. The authors have no conflict of interest. 
Disclosure: L. De Groef, None; I. Van Hove, None; E. Dekeyster, None; I. Stalmans, None; L. Moons, None 
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Figure
 
IOP is kept under control by an MMP-based feedback mechanism, regulating outflow resistance of the trabecular meshwork. (a) Homeostatic ECM turnover in the trabecular meshwork is actualized by constitutive expression of MMP-1, ‐2, ‐3, ‐9, ‐12, and ‐14, as well as TIMP-2. (b) Mechanical distortions, provoked by IOP elevations, are sensed by trabecular meshwork cells via ECM-integrin interactions and result in the upregulation of MMP-2, ‐3, and ‐14 secretion, while reducing TIMP-2, via an mTOR-mediated intracellular signaling cascade. Note: Outflow resistance is largely generated in the juxtacanalicular portion of the trabecular meshwork (JCT); however, MMP production and function are not exclusive to the JCT portion of the trabecular meshwork, as is depicted in the drawing, but may also occur on the cells of the corneoscleral portion of the meshwork (CSM). SC, Schlemm's canal.
Figure
 
IOP is kept under control by an MMP-based feedback mechanism, regulating outflow resistance of the trabecular meshwork. (a) Homeostatic ECM turnover in the trabecular meshwork is actualized by constitutive expression of MMP-1, ‐2, ‐3, ‐9, ‐12, and ‐14, as well as TIMP-2. (b) Mechanical distortions, provoked by IOP elevations, are sensed by trabecular meshwork cells via ECM-integrin interactions and result in the upregulation of MMP-2, ‐3, and ‐14 secretion, while reducing TIMP-2, via an mTOR-mediated intracellular signaling cascade. Note: Outflow resistance is largely generated in the juxtacanalicular portion of the trabecular meshwork (JCT); however, MMP production and function are not exclusive to the JCT portion of the trabecular meshwork, as is depicted in the drawing, but may also occur on the cells of the corneoscleral portion of the meshwork (CSM). SC, Schlemm's canal.
Table 1
 
Overview of the Available Data on MMP/TIMP Expression in the Trabecular Meshwork
Table 1
 
Overview of the Available Data on MMP/TIMP Expression in the Trabecular Meshwork
Expression Pattern Experimental Set-up Reference(s)
MMP-1 Basal MMP-1 expression in the TM Human and bovine TM cell culture, human TM explant culture, human corneoscleral explant culture 11, 14
MMP-1 expression is decreased in the TM after exposure to corticosteroids Human TM culture 52
MMP-2 Basal MMP-2 expression in the TM Human and bovine TM cell culture, human TM explant culture, human corneoscleral explant culture 11, 14
Punctuate MMP-2 immunostaining pattern over the surface and in the cytoplasm of TM cells Human TM cell culture 15
MMP-2 expression in the TM cells colocalizes to podosome- or invadopodia-like structures Human and porcine TM cell culture, human and porcine anterior segment organ culture 22
MMP-2 activity is increased in the TM within 24–72 hours post mechanical stretching, proportional to the degree of stretching Human, bovine, and porcine TM cell culture 12, 15, 21
MMP-2 activity is decreased in the TM of POAG patients Human TM cell culture (POAG) 26
MMP-3 Basal MMP-3 expression in the TM Human and bovine TM cell culture, human corneoscleral explant culture 11, 14, 15
MMP-3 expression is increased in the TM within 24–72 hours post mechanical stretching Human and bovine TM cell culture 19, 21
No changes in MMP-3 expression on mechanical stretching of the TM Human TM cell culture 15
MMP-3 expression in anterior segment is increased in response to elevated IOP Human perfused anterior segment organ culture 18
MMP-9 Basal MMP-9 expression in the TM Human and bovine TM cell culture, human corneoscleral explant culture 11, 15
No basal MMP-9 expression in the TM Human TM cell culture, human TM explant culture 14
Elevated IOP decreases MMP-9 activity in TM cells Human TM cell culture 23
MMP-9 activity is decreased in the TM of POAG patients Human TM cell culture (POAG) 26
MMP-10 MMP-10 expression in the TM is increased upon mechanical stretching Human TM cell culture 19
MMP-11, MMP-12 Basal MMP-11 and ‐12 expression in the TM Human TM cell culture, human TM explant culture 14
MMP-14 Basal MMP-14 expression in the TM Human TM cell culture, human TM explant culture 14
Punctuate MMP-14 immunostaining pattern over the surface and in the nuclei of TM cells Human TM cell culture 15
MMP-14 expression in TM cells colocalizes to podosome- or invadopodia-like structures Human and porcine TM cell culture, human and porcine anterior segment organ culture 22
MMP-14 expression in the TM is increased within 24-72 hours post mechanical stretching Human and porcine TM cell culture 12
MMP-15, MMP-16, MMP-17, MMP-19, MMP-24 Basal MMP-15, ‐16, ‐17, ‐19, and ‐24 expression in the TM Human TM cell culture, human TM explant culture 14
TIMP-1 Basal TIMP-1 expression in the TM Human and bovine TM cell culture, human TM explant culture, human corneoscleral explant culture 11, 14
TIMP-1 expression levels remain unchanged during 72 hours of mechanical stretching Bovine TM cell culture 21
Elevated IOP increases TIMP-1 expression in TM cells Human TM cell culture 23
TIMP-2 Basal TIMP-2 expression in the TM Human TM cell culture, human TM explant culture 14
Cytoplasmic and somewhat “fibril-associated” TIMP-2 immunostaining pattern in TM cells Human TM cell culture 15
TIMP-2 expression is strongly decreased in the TM within 24–48 hours post mechanical stretching Human TM cell culture 15
TIMP-2 expression remains unchanged during 72 hours of mechanical stretching Bovine TM cell culture 21
TIMP-3, TIMP-4 Basal TIMP-3 and ‐4 expression in the TM Human TM cell culture, human TM explant culture 14
Table 2
 
Overview of the Available Data on MMP/TIMP Expression in Aqueous Humor
Table 2
 
Overview of the Available Data on MMP/TIMP Expression in Aqueous Humor
Expression Pattern Experimental Set-up Reference(s)
MMP-2 MMP-2 is constitutively expressed in the AH, mainly in its proform Human AH samples 36
MMP-2 expression in the anterior segment is increased in response to elevated IOP Human perfused anterior segment organ culture 20
MMP-2 expression in the AH positively correlates with IOP in PEXG patients Human AH samples 35
The TIMP-2/MMP-2 ratio is increased in the AH of POAG, PEXS and PEXG patients Human AH samples 34, 36
Total MMP-2 expression is increased in the AH of USG, PEXS, PEXG, and POAG (not significant), but not CACG or NTG, relative to cataract, while levels of active MMP-2 are decreased; MMP-2 is increasingly converted to its active form in the AH of USG, whereas in PEXS, PEXG, and POAG, MMP-2 is mainly found in its latent form or bound to complexes with TIMPs Human AH samples 37, 38, 41
Latent MMP-2 expression is increased in the AH of glaucoma samples as compared with normal AH samples, whereas active MMP-2 is increased in the iridocorneal angle tissue Canine AH and iridocorneal angle tissue samples 33
MMP-3 MMP-3 expression in the anterior segment is increased in response to elevated IOP Human perfused anterior segment organ culture 18
Total MMP-3 expression is increased in the AH of PEXS, PEXG, and POAG (not significant), relative to cataract Human AH samples 38
MMP-8 MMP-8 expression is increased in the AH of USG, relative to POAG and cataract; MMP-8 is increasingly converted to its active form in the AH of USG, whereas in POAG and cataract, MMP-8 is mainly found in is latent form Human AH samples 37
MMP-9 MMP-9 expression is increased in the AH of USG, relative to POAG and cataract; MMP-9 is increasingly converted to its active form in the AH of USG, whereas in POAG and cataract, MMP-9 is mainly found in its latent form Human AH samples 37
Latent MMP-9 is increased in the iridocorneal angle tissue of glaucoma samples, as compared with normal samples, and is associated with glaucoma status Canine AH and iridocorneal angle tissue samples 33
MMP-10 MMP-10 expression in the anterior segment is increased in response to elevated IOP Human perfused anterior segment organ culture 20
MMP-13, MMP-14 MMP-13 and ‐14 expression is increased in the AH of USG, relative to POAG and cataract; MMP-13 and ‐14 are increasingly converted to their active form in the AH of USG, whereas in POAG and cataract, MMP-13 and ‐14 are mainly found in their latent form Human AH samples 37
TIMP-1 Total TIMP-1 expression is increased in the AH of PEXS, PEXG, and POAG (not significant), relative to cataract Human AH samples 38
TIMP-2 TIMP-2 expression in the AH negatively correlates with IOP in PEXG patients Human AH samples 35
The TIMP-2/MMP-2 ratio is increased in the AH of PEXG patients Human AH samples 34, 38
TIMP-2 expression is increased in the AH of USG, PEXS, and PEXG patients Human AH samples 36, 38
TIMP-2 expression is elevated in the AH of USG, relative to POAG and cataract Human AH samples 37
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