Is the corneal degradation in keratoconus caused by matrix-metalloproteinases?

Abstract

The thinning of the cornea that occurs in keratoconus has been well described; however, the mechanism of tissue degradation remains unknown. Elevated proteinase activity is one possibility and approximately 20 publications over the last 20 years have addressed this hypothesis. Early studies reported increased collagenase and gelatinase activities in the medium of keratoconus corneal cultures. After the characterization of the matrix metalloproteinase (MMP) enzymes, studies focused on the expression of specific MMPs, in particular the gelatinases, MMP‐2 and MMP‐9. Matrix metalloproteinase‐2 was found to be the major MMP of the cornea and was constitutively produced in normal tissue, whereas MMP‐9 expression was induced by various stimuli, including phorbol esters and even tissue culturing. These studies suggested that there were no differences in the amounts or states of activation of MMP between normal and keratoconus corneas, although the amounts of some proteinase inhibitors, including tissue inhibitors of metalloproteinases, α‐1‐proteinase inhibitor and α‐2‐macroglobulin, were decreased in keratoconus. Most recently, the lysosomal proteinases, cathepsin B and cathepsin G were reported to be elevated in keratoconus corneas, and it is possible that it was cathepsin activity, not MMP activity, that was measured in some early studies. Nevertheless, there are now about 20 human MMPs identified and it is possible that some of these, other than the well known collagenase (MMP‐1) and gelatinases (MMP‐2 and MMP‐9), could be implicated in the pathology of keratoconus. Studies have begun to address more recently described MMPs and it has been reported that the membrane‐bound MT1‐MMP (MMP‐14), which activates latent MMP‐2, was found to have increased expression in keratoconus corneas, whereas the stromelysins, MMP‐3 and MMP‐10, were not.

Inflammatory Response to Contact Lenses in Patients With Keratoconus Compared With Myopic Subjects

“…The tears may be a conduit for some of the pathogenic protagonists of keratoconus, such as IL-6, TNFa, or MMP-9.Sporadic increases in the concentration of these molecules might be sufficient to cause a slowly progressive ectasia. 25 On the basis of these findings, we can formulate both a conclusion and a consequence. The conclusion is that a higher level of inflammatory response to mild aggression is found in keratoconus in comparison to normal corneas; the consequence is that wearing CLs may negatively affect the evolution of the ectasia.…”

Cytokine Expression in Keratoconus and its Corneal Microenvironment: A Systematic Review

“…48 Also, the thinning and ectasia of the cornea suggests direct degradation of the corneal collagen that could be caused by enzymes such as MMPs. 53,54 In the human cornea, the MMP activity is in part regulated via IL-1β. Therefore, IL-1α and IL-1β have various pathogenic roles in KC that may be endogenously higher expressed in genetically prone individuals and are extensively secreted when the cornea is minimally damaged.…”

What Causes Keratoconus?

“…9,10 Activity of matrix metalloproteinases has been implicated as a cause of the stromal degradation in keratoconus. 11 Alterations of tissue inhibitors of metalloproteinases are seen 12 additionally, possibly promoting corneal stromal breakdown. Transcription factor Sp1, which plays a role in gene expression, is not activated in normal mature cornea but is found in abundance in keratoconus epithelium.…”