In the last few years, references to matrix metalloproteinases (MMPs) have surfaced repeatedly in the ophthalmic literature, often in reference to ocular surface disease. This column will look at what these enzymes are and why they may be of interest to clinicians who deal with ocular surface disease.
What Are MMPs?
To define matrix metalloproteinases, let us walk backward through the term. A proteinase is simply an enzyme that breaks down proteins. The specific proteinases we call MMPs work through an interaction with zinc, earning them the title of metalloproteinases.
Metalloproteinases are secreted in zymogen form, meaning that they are inactive (proenzymes) when they are secreted by a cell. They become active only when a piece is cleaved from the proenzyme to create the active form, a process that takes place in the extracellular environment. This cleavage involves zinc that is incorporated into the MMP molecule.
The matrix part of the term derives from their function—these proteinases work on protein constructs that are normally part of the matrix of the body.
At least 28 MMPs have been identified. As a class, MMPs function in tissue remodeling; and among the MMPs are collagenases, gelatinases, and stromelysins (which cleave extracellular matrix proteins). The MMPs of greatest interest with respect to the eye are those that degrade corneal collagen or gelatin type structures, in particular MMP-9.
MMPs may take part in normal corneal homeostasis—the ongoing deposition and remodeling of ocular tissue. That process is healthy and well regulated, and exists at an extremely low level in healthy eyes. MMPs jump in number and become of considerable interest when inflammation causes unregulated MMP activity.
A variety of factors will trigger MMP release. For example, because androgens tend to suppress inflammation, a drop in androgen levels can trigger inflammation, setting off the release and activation of MMP-9. Of course, infection can stimulate inflammation; and thermal injury (burns) to the ocular surface will set off the release of collagenases, elastases, and a number of other remodeling enzymes.
The Significance of MMP-9
Dry eye disease has an important inflammatory component, and so the detection of inflammation can be a useful adjunct in dry eye diagnosis. This would be helped by a test for a simple inflammation marker. The levels of any number of biochemicals—including cytokines, chemokines, eicosanoids, and enzymes like MMP-9—increase or decrease during the inflammatory process. And many of these could, in theory, serve as a marker for inflammation. MMP-9 is a matrix-destroying enzyme, and its presence indicates a significant level of inflammation; hence its potential value in diagnosis.
That MMP-9 is an inflammatory marker is both the good news and the bad news for those who would use its presence to detect dry eye disease. There is considerable diagnostic value in knowing that MMP-9 levels are elevated, since elevated MMP-9 indicates the presence of a significant pathologic process—using simple tests one would not expect to find MMP-9 in a healthy eye. The good news is that MMP-9 is a good marker for inflammation.
The bad news is that elevated MMP-9 levels are only a sign of inflammation. They are not a marker for any specific cause of inflammation. A simple test for MMP-9 cannot, by itself, be considered a test for dry eye disease because many other pathologic processes also lead to ocular surface inflammation. For example, ocular rosacea patients have been clearly shown to have elevated MMP-9 levels, and Acera and coworkers have reported elevated MMP-9 levels in patients with blepharitis, ocular allergic disease, and conjunctivochalasis, as well as dry eye.1,2
What the MMP-9 test can say is that significant ocular surface inflammation is present and antiinflammatory treatment has a good chance of being successful. But I take issue with those who would say that just showing the presence of MMP-9 on the ocular surface or in the tears indicates dry eye disease.
A new rapid, in-office immunoassay (InflammaDry®; RPS) can detect MMP-9 in a fluid sample drawn from the inferior palpebral conjunctiva. The test is simple and easy, and company data indicates that it is accurate. The key to its value will be the appropriate interpretation of its results. As with the treatment of dry eye disease, there is no one-step “silver bullet” that will yield a sure result.
Gary N. Foulks, MD, FACS, is the Arthur and Virginia Keeney professor of ophthalmology, University of Louisville, Louisville, KY, and is editor-in-chief of The Ocular Surface.
1. Afonso AA, Sobrin L, Monroy DC, et al. Tear fluid gelatinase B activity correlates with IL-1alpha concentration and fluorescein clearance in ocular rosacea. Invest Ophthalmol Vis Sci. 1999 Oct;40(11):2506-12.
2. Acera A, Rocha G, Vecino E, et al. Inflammatory markers in the tears of patients with ocular surface disease. Ophthalmic Res. 2008 Oct;40(6):315-21.