New discoveries on the roles of matrix metalloproteinases in ocular cell biology and pathology.

Matrix metalloproteinases (MMPs) are a family of extracellular endoproteinases that are receiving considerable attention from biologists, clinicians, and the pharmaceutical industry. MMPs play a major role in normal development, reproduction, and tissue remodeling. In addition, these molecules are involved in a number of pathogenic processes including cancer, arthritis, angiogenesis, and wound healing. Recently there have been a number of important discoveries on the role of MMPs in the eye. The purpose of this article is to highlight several of these recent discoveries, including the roles of MMPs in the regulation of aqueous humor outflow, Sorby's fundus dystrophy and age-related macular degeneration (AMD), and ocular angiogenesis. This article is not meant to be a comprehensive review of MMPs in the eye, and many other interesting aspects of MMPs in the eye are not discussed because of space limitations. To date there are at least 17 different MMPs and 4 endogenous tissue inhibitors of matrix metalloproteinases (TIMPs) expressed in humans.' MMP activity is regulated by transcriptional control, by proenzyme activation, and by the presence and location of endogenous TIMPs. MMPs are involved in the degradation of a variety of extracellular matrix (ECM) molecules, and ECM homeostasis is thus determined to a great extent by the balance between MMP and TTMP expression. The nomenclature for the MMP system is often confusing because MMPs have several names. The major MMPs and TIMPs discussed in this article are as follows: MMP-1 (collagenase), MMP-2 (getatinase A), MMP-3 (stromelysin-1), MMP-9 (gelatinase B), and TIMPs 1 to 3. Several lines of evidence suggest that MMPs are involved in the regulation of intraocular pressure GOP) by affecting aqueous humor outflow resistance. IOP is the result of the interplay between the rate of aqueous humor formation, aqueous humor outflow resistance, and episcleral pressure. In the past, attempts to regulate IOP concentrated on the control of aqueous humor formation, whereas aqueous outflow was considered to be a passive process. However, the ocular hypertension in primary open angle glaucoma does not involve excess aqueous humor production but is due to increased aqueous outflow resistance and is associated with increased deposition of ECM material in the aqueous outflow pathway. Certain glaucoma therapies (e.g., pilocarpine, epinephrine, and prostaglandins) increase aqueous humor outflow, but do not address the underlying glaucomatous pathogenic process(es) in