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Home , Aggrecan, Biglycan, Brevican, CTGF, Decorin, Laminin

Supplementary Table S1. Matrix classification.

MMPs Classification Traditional Numerical Chromosomal Group of sustrates General biological Reported eye Eye implicated processes Ref. classification classification localization effect localization EMC Substrates AMD Eye Processes (I, II, III, VII, VIII, X), Entactin, , - Development of soft drusen- early AMD , , - The directional shift in the MMP-1/TIMP-1 , , Mediate normal ratio is associated with increased type I , BM-40, ECM turnover, collagen degradation. Potential mechanism , , migration of o Corneal contributing to the pathogenesis of exudative Entactin/ , keratinocytes, re- [41,50,54,55] stroma AMD , , CTGF, epithelialization, o Optic Link , Myelin basic migration, nerve head protein, Fibrin, o Cultured -1 MMP-1 11q22-q23 Non-EMC Substrates aggregation, Non-AMD Eye Processes RPE cells Pro-MMP-1, Pro-MMP-2, increase in the o Trabecul proMMP-9, MCP-1, MCP- bioavailability of ar meshwork - Corneal wound repair 3, MCP-4, SDF, Pro-1L- 1β, IGF-1, cell o Aqueous - Glaucomatous optic nerve head damage 1L-1β, IL-8, IGFBP-2, proliferation, pro- humor - Epiretinal and subretinal membranes in PVR IGFBP-3, Pro-TNF-α, inflammatory effect, - Activation of at the head of CXCL5, CXCL11 and PARP1 pterygium precursor, Casein, C1q, activation - Overexpression is related to poor RB Serum amyloid A protein, [49,55–58] differentiation α1-Proteinase Inhibitor,

α1-Anti-Chymotrypsin, α2-Macroglobulin EMC Substrates The activation of o Corneal AMD Eye Processes Collagen (I–III, V, VII, VIII, osteoclasts, the stroma Collagenase-2 MMP-8 11q21-q22 - Several roles in ocular inflammation and X), Gelatin, Fibronectin, enhancement of o Tear remolding, including cleavage Laminin Subunit Gamma- collagen affinity, β- samples 2, Entactin, Aggrecan, FGF release, anti- o Vitreous degradation ECM components and regulation [55,58] Tenascin, Brevican Core inflammatory samples of activity Protein Precursor, Myelin activity Basic Protein, Fibrinogen Non-EMC Substrates Non-AMD Eye Processes Pro-MMP-8, MCP-1, Pro- TNF-α, IL-8, L-, IGFBP, CXCL5, CXCL10, - Xerophthalmia CXCL11, Substance P, - In RD models low MMP-8 expression may Angiotensin I, Angiotensin lead to inhibition of RPE apoptosis and II, , - B1, proliferation C1-Inhibitor, α1- - Uveal Melanocytes may participate remolding [55,58,59] Proteinase Inhibitor, α2- and inflammatory process via MMP-8 Macroglobulin

EMC Substrates Non-AMD Eye Processes Colagen (I-III, VI, VII, IX, X, XIV), Gelatin, Fibronectin, Laminin Subunit Gamma-2, , - MMP-13 produced by marrow–derived Collagen telopeptides, Ability of cleavage cells appear to be important in experimental SDF, Brevican, Fibrillin, intersticial choroidal neovascular membrane formation Aggrecan, Perlecan, CTGF, I, II and III, as well [55,58,60] Large Tenascin-C, as other ECM o Corneal Collagenase-3 MMP-13 11q22.3 , SPARC, molecules. epithelium , Fibrinogen Key regulator of Non-EMC Substrates choroidal Non-AMD Eye Processes Pro-MMP-9, Pro-MMP-13,

MCP-3, SDF, Pro-TNF-α, - Corneal CXCL5, Factor XII, Casein, - Increased expression in experimental RD C1q, α1-Anti- [55,56,58,61,6 - The modulation of could have Chymotrypsin, α2- 2] implications for the development of PVR Macroglobulin - MMP-13 expressed by pterygium tissues may induce collagen II and III remodeling in pterygium stroma (pterygium recurrence)

Gelatinases [32,41,51– 53,55,58,63– 65]

EMC Substrates AMD Eye Processes Collagen (I, II, III, IV, V, The growth of VII, X, XI), Gelatin, Elastin, , cell Fibronectin, migration, the Entactin/Nidogen-1, differentiation of Aggrecan, Decorin, mesenchymal cell o - Critical role in the early AMD development, Fibrillin, 2, with inflammation (all layers) due to the accumulation of deposits under the Laminin-5, Tenascin, phenotype, o Vitreous RPE and increased synthesis of IV type SPARC, Vitronectin, enhancement of o Optic collagen -1, Galectin-3, collagen affinity, nerve head -Total levels of active MMP-2 are significantly A MMP-2 16q13 , BM-40, Brevican, cell proliferation, o Interphot reduced in BM from AMD patients Neurocan, CTGF, CSPG-4, migration of oreceptor - Increase plasma levels in PCV , PCPE-1, epithelial cells, anti- matrix Link Protein, Osteonectin, inflammatory, an o Lens Myelin Basic Protein, increase in the epithelium Biglycan, Fibrin, bioavailability of Fibrinogen TGF-b, neuronal Non-EMC Substrates Non-AMD Eye Processes apoptosis leading to Pro-MMP-1, Pro-MMP-2, - Corneal wound repair and development neurodegeneration Pro-MMP-13, MMP-12, - Glaucomatous optic nerve head damage MCP-3, SDF, Pro-TGF- β1, - Vitreous liquefaction Pro-TNF-α, Pro-IL-1β, - Cataract formation CXCL5, IGFBP-3, IGFBP-4, - Uveitis IGFBP-5, IGFBP-6, 14-3-3 - PDR and new blood vessels formation protein, Big -1, - MMP-2 inhibition may reduce VEGF [55,57,58,63– Cystatin C, -like expression and, thus, angiogenesis in 65] 1, Alpha- actin-2, retinoblastoma cell lines (Overexpression is Pregnancy zone protein, related to poor RB differentiation) Substance P, Decorin, IGFBP, Plasminogen S100A10, proEMAP/p43, FGF-R1, MMIF, -2, Plasminogen, α1- Proteinase Inhibitor, α1- Anti-Chymotrypsin, α2- Macroglobulin EMC Substrates AMD Eye Processes Collagen (I, IV, V, XI, and Collagen affinity XIV), Gelatin, Elastin, enhancing, pro- Vitronectin, Laminin, inflammatory and o Corneal - Increased plasma levels in GA in AMD Decorin, Fibrillin, anti-inflammatory epithelium and - Development of CNV as part of AMD Fibronectin, SPARC, activity, tumor cell stroma pathogenesis [32,41,51– Aggrecan, Link Protein, resistance, IL-2 o Lens - Increase plasma levels in PCV 53,55,58] Galectin-1, Galectin-3, response reduction, epithelium - Total levels of active MMP-9 are significantly Versican, Decorin, hypertrophic o Retinal reduced in BM from AMD patients MMP-9 20q11.2-q13.1 Biglycan, Link Protein, ganglion Osteonectin, Myelin Basic apoptosis and the cells Protein, Fibrin, Fibrinogen subsequent o Iris Non-EMC Substrates incorporation of o Ciliary Non-AMD Eye Processes Pro-MMP-2, Pro-MMP-9, new units of body - Corneal ulcerations and neovascularization Pro-MMP-13, MCP-3, SDF, functional o vitreous - Vitreous liquefaction Pro-IL-8, Pro-TNF-α, Pro- - Cataract formation TGF-β2, Pro-IL-1β, Cell- - Uveitis surface IL-2Rα, CXCL5, CXCL9, CXCL10, CXCL11, - PDR and new blood vessels. An up regulation FGF-R1, CTAP-III/NAP-2, is associated with CNV. Might be involved in GROα, PF-4, beta- hemorrhagic transformation in patients [55,57,58,63– 2, IGFBP- 1, IGFBP-4, affected with PDR. Accelerate apoptosis of 66] Substance P, Angiotensin I, retinal capillary cells. Angiotensin II, ADAMTS- - MMP-9 inhibition may reduce VEGF 4, SERPINE2, Casein, C1q, expression and, thus, angiogenesis in TFPI, Plasminogen, α1- retinoblastoma cell lines (Overexpression is Proteinase Inhibitor, α2- related to poor RB differentiation) Macroglobulin - 17β-estradiol upregulates MMP-9 in the lacrimal gland and conjunctival epithelium, increasing activity in tears of dry subjects - Is linked to and contributes to rod death in RP model Stromelysins EMC Substrates Migration of cells, AMD Eye Processes Collagen (III, IV, V, VII, IX, epithelial cells X, XI), Gelatin, Collagen apoptosis, the Telopeptides, Elastin, formation of Fibronectin, Vitronectin, epithelial bubbles, -The directional shift in the MMP-3/TIMP-1 Laminin, Entactin/ epithelial– ratio is associated with increased type I Nidogen-1, Tenascin, mesenchymal collagen degradation. This may be an SPARC, Aggrecan, conversion, [41,55,58] o Corneal important mechanism contributing to the Decorin, Perlecan, -like stroma pathogenesis of early exudative AMD Stromelysin-1 MMP-3 11q23 Versican, Fibulin, Biglycan, elements o Optic Link Protein, Osteonectin, generation, the nerve head Myelin Basic Protein, collagen affinity Fibulin-2, Fibrin, enhancement, Fibrinogen release of bFGF, Non-EMC Substrates increase in the Non-AMD Eye Processes Pro-MMP-1, Pro-MMP-3, bioavailability of - Autocrine regulation of stromal collagenase in Pro-MMP-7, Pro-MMP-8, IGF-1, cell penetrating wounds [55,56,63,67] Pro-MMP-9, Pro-MMP- 13, proliferation, pro- - Glaucomatous optic nerve head damage MCP-1, MCP-2, MCP-3, inflammatory and - DR MCP-4, SDF, Pro-TNF-α, anti-inflammatory - MMP-3 deficiency reduces leukocyte L-selectin, Pro-HB- EGF, activity, increase the recruitment to the retina and vitreous cavity Pro-IL-1β, Perlecan, bioavailability of -Strong modulator of acute ocular Decorin, E-cadherin, TGF-β, disorder in inflammation in the posterior part of the eye IGFBP-3, Cm-Tf, Substance cells aggregation, - Activation of fibroblasts at the head of P, T-kininogen, Casein, increase in cell pterygium C1q, uPA, uPAR, invasiveness; Osteopontin, VEGFA, PAI, release of VEGF and Plasminogen, α2- bFGF, upregulation Antiplasmin, α1-Proteinase of , α1-Anti- Chymotrypsin, α2- Macroglobulin EMC Substrates Non-AMD Eye Processes Collagen (I, III, IV, V), Gelatin, Elastin, Fibronectin, Aggrecan, Generation of - Ocular surface diseases Brevican Hyaluronan and tumstatin, - Overexpression in diabetic Link Protein o Corneal Stromelysin-2 MMP-10 11q22.3-q23 , - Vitrectomy could be associated higher [55,68,69] 1, Proteoglycan, Link epithelium angiostatin, and concentrations of MMP-10 Protein, Fibrinogen endorepellin - PDR Non-EMC Substrates

Pro-MMP-1, Pro-MMP-7, Pro-MMP-8, Pro-MMP-9, Pro-MMP-10, Casein EMC Substrates The is Gelatin, Fibronectin, activated Collagen IV, Laminin, intracellularly by Aggrecan furin within the Stromelysin-3 MMP-11 22q11.2 Non-EMC Substrates constitutive o N/A - N/A [55] secretory pathway. Pro-MMP-11, IGFBP-1, Also, in contrast to Casein, Cm-Tf, α-actin-2, other MMP's, this PAI-2, α2-Antiplasmin, α1- enzyme cleaves Proteinase Inhibitor, α2- alpha 1-proteinase Macroglobulin inhibitor but weakly degrades structural of the ECM EMC Substrates AMD Eye Processes Collagen (IV, V, IX, X, XI), Gelatin, Elastin, Adipocyte Fibronectin, Vitronectin, differentiation, Laminin, Entactin/ - Ability to digest ECM components and cells collagen affinity Nidogen-1, Tenascin, surface molecules BLD associated with the enhancement, an [41,55,58] SPARC, Aggrecan, development of choroidal neovascularization increase in the Brevican, Galectin-3, Link secondary to AMD bioavailability of Protein, Decorin, Fibulin, IGF 1 and TGF-β, Versican, Osteonectin, cell differentiation, Myelin Basic Protein, abnormal cell Fibrin, Fibrinogen aggregation and o Corneal Non-EMC Substrates Non-AMD Eye Processes Matrilysin MMP-7 11q21-q22 increase in cells epithelium and Pro-MMP-1, Pro-MMP-2, invasiveness, stroma Pro-MMP-7, Pro-MMP-9, apoptosis induced Pro-TNF-α, Pro-α- by Fas receptor defensin, Cell surface activation, the effect - Corneal wound healing bound Fas-L, CXCL9, of pro- - pterygia (angiogenesis) CXCL11, IGFBP-1, IGFBP- inflammatory - Increase levels after anti-VEGF in retinal vein [41,55,70,71] 2, IGFBP-3, β4-integrin, E- activation of occlusion cadherin, Apo-A1, Apo- osteoclasts, - Elastic fibre degradation in patients with CII, CD95-L, Casein, Cm- vasoconstriction involutional ectropion and entropion Tf, Osteopontin, uPA, and Plasminogen, Decorin, α1- Proteinase Inhibitor, α2- Macroglobulin EMC Substrates May be involved in Non-AMD Eye Processes Metalloelastas o Corneal MMP-12 11q22.2-q22.3 Collagen (I, V, And IV), tissue injury and - Increased expression in RD [41,55,61,72] e epithelium Gelatin, Elastin, remodeling. Has - Corneal wound healing Fibronectin, Vitronectin, significant - May be involved in the ECM remodeling Laminin, Entactin, elastolytic activity - Kew regulator of infiltration and Osteonectin, Decorin, inflammation, contributing to retinal vascular Aggrecan, Biglycan, dysfunction and pathological angiogenesis. The Fibrillin, Myelin Basic increase or decrease of its levels facilities CNV Protein, Fibrin, Fibrinogen formation Non-EMC Substrates - The modulation of fibrosis could have Plasminogen, Pro-TNF-α, implications for the development of PVR ApoA-1, CXCL9, CXCL10, CXCL11, uPAR, vWF, Factor XII, TFPI, α1- Proteinase Inhibitor EMC Substrates Non-AMD Eye Processes Collagen IV, Gelatin, Fibronectin, Vitronectin, Fibrinogen Ability to digest o epithelial Matrilysin-2 MMP-26 11p15 Non-EMC Substrates ECM components - Expression in glioma is correlated with poor [55] conjunctiva cells Pro-MMP-9, Pro-MMP26, clinical outcome IGFBP-1, α1-Proteinase Inhibitor, α2- Macroglobulin EMC Substrates AMD Eye Processes Collagen XVIII, Amelogenin, May play a central - Not associated with the appearance of Enamelysin MMP-20 11q22.3 Ameloblastin, Aggrecan, role in tooth enamel o N/A [38] exudative AMD, but it could affect the size of Laminin, COMP formation the neovascular lesion Non-EMC Substrates Pro-MMP-20 (autolysis) Membrane-type MMPs (MT-MMP) EMC Substrates Anti-inflammatory, Non-AMD Eye Processes o Corneal Collagen (I, II and III), cell migration, the - Corneal infection, wound healing, inducing epithelium [41,49,55,61,7 MT-MMP-1 MMP-14 14q11-q12 Gelatin, Fibronectin, formation of renal corneal neovascularization (pro-angiogenic o Human 2] Tenascin, Vitronectin, tubules, epithelial factor) TM cell culture, Laminin, Entactin, cell migration, - Proliferative diabetic retinopathy Galectin-3, CTGF-L, adhesion reduction, human TM - Implications for ECM turnover Fibrillin, Aggrecan, flattening of the explant culture - Biomarker of angiogenic activity in PDR Perlecan, -1, cells reduction, - Keratinocyte migration , Myelin Basic trailers embryo to Protein, Fibrinogen the uterine Non-EMC Substrates epithelium Pro-MMP-2, Pro-MMP-13, - Activation MMP-2 Pro-MMP-14, MMP-14, MCP-3, SDF, Cell-surface CD44, RANKL, tTG, Pro- TNF-α, IL-8, HB-EGF, Factor XII, Pro-αv integrin chain, Apo-CII, Apo-E, α1- Proteinase Inhibitor, α2- Macroglobulin EMC Substrates Non-AMD Eye Processes Fibronectin, Tenascin, Entactin, Laminin, Aggrecan, Perlecan, o Human Proteoglycan, Myelin Basic Adhesion and cell TM cell culture, MT-MMP-2 MMP-15 15q13-q21 -Could play a modulatory role in IOP [55,73,74] Protein flattering reduction human TM Non-EMC Substrates explant culture Pro-MMP-2, Cell- surface bound tTG, Pro-TNF-α EMC Substrates Non-AMD Eye Processes Collagen III, Gelatin, Fibronectin, Vitronectin, o Human Laminin, Myelin Basic Adhesion and cell TM cell culture, MT-MMP-3 MMP-16 8q21 -Could play a modulatory role in IOP [55,73,74] Protein flattering reduction human TM homeostasis Non-EMC Substrates explant culture Pro-MMP-2, Cell-surface bound tTG, Pro-TNF-α, -suppressor KiSS-1 EMC Substrates May be involved in Non-AMD Eye Processes Gelatin, Fibrin, Fibrinogen, the activation of Myelin Basic Protein membrane-bound Non-EMC Substrates precursors of o Human growth factors or TM cell culture, MT-MMP-4 MMP-17 12q24.3 inflammatory -Could play a modulatory role in IOP [55,73,74] human TM Pro-MMP-2, Pro-TNF-α, mediators, such as homeostasis explant culture HB-EGF, ADAMTS4 TNF-α. May also be Peptidase involved in tumoral process.

EMC Substrates Involved in cell-cell Non-AMD Eye Processes Fibronectin, Gelatin, interactions o Human Chondroitin Sulphate between nociceptive TM cell culture, MT-MMP-5 MMP-24 20q11.2 Proteoglycan, Dermatan neurites and mast -Could play a modulatory role in IOP [55,73,74] human TM Sulphate Proteoglycan cells. May play a homeostasis explant culture Non-EMC Substrates role in axonal Pro-MMP-2, KiSS-1 growth Tissue inhibitor of metalloproteinases (TIMPs) AMD Eye Processes - Potential role for MMPs in the development of o Corneal CNV in AMD. TIMP-1 promotes VEGF- cells, epithelium and induced Increased neovascularization in the retina expression has been [16,17,51,52] Metalloprotei All types of MMPs (MMP- o Optic - Increase levels in patients with GA in AMD found associated nase inhibitor TIMP-1 Xp11.3 1, MMP-3, MMP-7 and nerve head - Lower TIMP-3 levels are associated with with worse 1 MMP-9) and MT-MMPs o Retinal higher TIMP-1 levels and the presence of GA in prognosis of tumors ganglion cells AMD such as laryngeal o Vitreous carcinoma or o IPM Non-AMD Eye Processes -Increased expression in experimental RD and [61,72,75,76] PVR - Corneal wound healing, keratoconus - POAG

AMD Eye Processes

Connective tissue - In combination with MMP-14, is involved in cells, macrophages o Corneal [16,17,51,52] regulation of MMP-2. High levels of TIMP-2 Important role in epithelium inhibit MMP-2 activity- Potential role in AMD Metalloprotei hippocampus and o RPE All types of MMPs (MMP- nase inhibitor TIMP-2 17q25.3 cognitive function o Retinal 2) Non-AMD Eye Processes 2 It has an ganglion cells - Potential Biomarkers of RB progression independent o IPM - Increased expression in experimental RD and antiangiogenic o Vitreous [57,61,72] PVR effect - Corneal wound healing, keratoconus - POAG AMD Eye Processes Blocks the - Excess TIMP-3, may retard BM renewal and development of result in the thickening. neovascularization - Reduced TIMP-3 production, causes an by inhibiting the o RPE increase in the amounts of various collagens binding of VEGF to o BM Metalloprotei All types of MMPs and development of early dry AMD. [16,17,51,52] the VEGF receptor, o Corneal nase inhibitor TIMP-3 22q12.3 ADAM Also increases ADAM/ADAMTs, which can be Regulate local MMP epithelium 3 ADAMTS implicated in CNV formation in AMD to maintain rate of o Vitreous -Mutations in this have been associated turnover and limit o IPM with the autosomal dominant disorder SFD choroidal growth

Fibroblasts, Non-AMD Eye Processes synovial cells [17,77] - Potential role in RP Role in the Non-AMD Eye Processes Metalloprotei regulation of MMP-1, MMP-2, MMP-3, o Aqueous nase inhibitor TIMP-4 3p25.2 platelet [76] MMP-7 and MMP-9 humor - POAG 4 aggregation, hormonal and endometrial tissue remodeling Ref: references. MMP-1: matrix 1; BM-40: basement-membrane protein 40; CTGF: CCN2 or connective tissue ; ECM: ; IGF-1: -like growth factor 1; MCP-1: Monocyte chemoattractant protein-1; SDF: stromal cell derived factor ; AMD: age-related macular degeneration; RPE: retinal pigment epithelium; IGFBP: insulin like growth factor binding protein; CXCL11 precursor: C-X-C motif chemokine 11; PARP1: Poly [ADP-ribose] polymerase 1; TNF-α : alpha; TIMP-1: metalloproteinase tissue inhibitor 1 ; RB: retinoblastoma; MMP-8: 8; β-FGF: basic growth factor; RD: retinal detachment; MMP-13: matrix metalloproteinase 13; SPARC: Secreted protein acidic and rich in ; PVR: proliferative vitreoretinopathy; MMP-2: matrix metalloproteinase 2; CSPG-4: ; PCPE-1: procollagen c-proteinase enhancer 1; PCV: polypoidal choroidal vasculopathy; PDR: proliferative diabetic retinopathy ; VEGF: vascular endothelial growth factor; proEMAP/p43: tumour-derived cytokine; FGF-R1: fibroblast 1; MMIF: macrophage migration inhibitory factor; TGF- b: transforming growth factor beta; MMP-9: matrix metalloproteinase 9; IL: ; FGF-R1: receptor 1; CTAP-III/NAP-2: connective tissue-activating III/neutrophil-activating peptide-2; GROα: growth-regulated oncogene alpha; PF-4: ; ADAMTS-4: a and metalloproteinase with thrombospondin motifs; SERPINE2: family E member 2; TFPI: tissue factor pathway inhibitor; CNV: choroidal neovascularization; GA: geographic atrophy; RP: retinitis pigmentosa; MMP-3:matrix metalloproteinase 3; Pro-HB- EGF: -binding -like growth factor; Cm-Tf: carboxymethylated transferrin; uPA: urokinase plasminogen activator; uPAR: urokinase plasminogen activator receptor ; MMP-10: matrix metalloproteinase 10; MMP-11: matrix metalloproteinase 11; N/A: not available; PAI-2: plasminogen activator inhibitor-2; MMP-7: matrix metalloproteinase 7; BLD: basal laminar and linear deposits; Fas-L: Fas ; Apo-A1: apolipoprotein A1; Apo-CII: apolipoprotein C-2;CD95-L: cluster of differentiation-95 ligand; MMP-12: matrix metalloproteinase 12; vWF: von Willebrand factor; MMP-26: matrix metalloproteinase 26; MMP-20: matrix metalloproteinase 20; COMP: oligomeric matrix protein; MMP-14: matrix metalloproteinase 14; CTGF-L: connective tissue growth factor-like; RANKL: receptor activator of nuclear factor kappa-Β ligand; tTG: tissue transglutaminase; TM: trabecular meshwork; MMP-15: matrix metalloproteinase 15; IOP: intraocular pressure; MMP-16: matrix metalloproteinase 16; Metastasis-suppressor KiSS-1: metastasis-suppressor 1; MMP-17: matrix metalloproteinase 17; MMP-24: matrix metalloproteinase 24; IPM: interphotoreceptor matrix; ADAM: a disintegrin and metalloproteinase; ADAMTS: A Disintegrin-like And Metalloproteinase with ThromboSpondin motifs; TIMP-2: metalloproteinase tissue inhibitor 2; TIMP-3: metalloproteinase tissue inhibitor 3; TIMP-4: metalloproteinase tissue inhibitor 4; SFD: Sorsby's Fundus Dystrophy; POAG: primary open angle glaucoma.