Thus far, 24 MMPs have been identified in vertebrates and grouped into four main subfamilies based on their specificity for different extracellular matrix components, among them the collagenases (MMP-1, -8, -13), gelatinases (MMP-2, -9), stromelysins (MMP-3, -10, -11), membrane-type MMPs, and others including matrilysin (MMP-7) and metalloesterase (MMP-12).
41 The collagenases degrade fibrillar collagens types 1, 2, and 3; the gelatinases degrade denatured collagens (gelatins) and native collagen types 4, 5, and 7 and also elastin and vitronectin; stromelysins cleave type 4 collagen, proteoglycans, fibronectin, laminin, and elastin. MMPs are synthesized and secreted as inactive proenzymes and are activated by proteolysis. MMP activities are strictly regulated by unspecific plasma inhibitor (α-macroglobulins) and specific TIMPs.
41 Four TIMPs have been identified that have the capacity to inhibit all active MMPs.
42 TIMP-1 controls most MMPs, particularly MMP-1, whereas TIMP-2 is the major inhibitor of MMP-2. Functionally, MMPs have been implicated in the normal matrix remodeling process, such as embryonic development, morphogenesis, tissue homeostasis, and wound healing. In contrast, a lack of balance between the activities of MMPs and those of TIMPs has been associated with a number of pathologic conditions, including inflammatory diseases,
43 cancer,
44 45 cardiovascular disease,
46 47 neurologic disease,
48 49 fibrotic conditions, and several eye diseases, among them glaucoma. In terms of roles of ECM metabolism in the pathogenesis of glaucoma, Haung et al.
50 examined normal aqueous humor by zymography and found several active forms of MMPs present in the aqueous and their endogenous inhibitors, TIMPs. In a different study, it was revealed that an increase of TIMPs was found only in the aqueous humor of POAG-affected eyes among aqueous humor specimens from eyes with POAG, eyes with secondary forms of glaucoma, and control eyes. Furthermore, adding aqueous samples to the tissue cultures significantly increased collagen synthesis.
51 Based on these data, the author suggested that this effect might have contributed to an increased deposition of collagen in the trabecular meshwork in the pathogenesis of POAG. Alternatively, increased MMP-1 expression was found in retinal ganglion cells of glaucomatous eyes, and MMP-1, -2, and -3 were found all over the optic nerve heads and in the postlaminar region, especially in eyes with normal pressure glaucoma compared with control eyes.
52 53 In terms of MMP expression within ocular surface tissue, Li et al.
24 reported the overexpression of MMP-1 and -3 in conjunctivochalasis fibroblast and suggested that this caused excessive degradation of conjunctival matrix and Tenon’s capsule, resulting in the looseness of conjunctival tissue characteristic of this disease. In our recent study,
26 the introduction of MMP-3 cDNA into conjunctiva caused significant effects on postoperative bleb survival and effectively maintained lower IOP levels. Furthermore, such MMP-3 transfection by EP caused effective expression within conjunctival epithelium until at least 30 days after transfection. These observations suggested that the reduction of subepithelial collagen density and the accumulation of ECM by the upregulation of MMP expression may have a beneficial effect on the survival of postoperative filtering blebs. Mietz et al.
40 reported that compared with timolol administration, latanoprost administration caused the upregulation of MMP-3 and histopathologic changes showing decreased subepithelial density in rabbit conjunctiva. Our present study revealed that, in addition to latanoprost, carteolol, nipradilol, levobunolol, bunazocin HCl, and brimonidine demonstrated upregulation and downregulation of MMP and TIMP expression. Therefore, these antiglaucoma drugs may have beneficial effects on glaucoma-filtering surgery by modulating ECM metabolism.