Metalloproteinases & corneal melting

Post-op corneal melting
Source: Dennis Brooks, M.D.

Matrix metalloproteinases (MMPs) are closely linked to corneal melting associated with primary Sjörgen’s syndrome (pSS), and more treatment strategies should take this into account, new research claims.
Our study examined extremely severe cases of corneal melting associated with pSS, and has elucidated the participation of some MMPs in this destructive process,” reported lead study author Kristyna Brejchova, Laboratory of the Biology and Pathology of the Eye, Institute of Inherited Metabolic Disorders, General Teaching Hospital and Charles University, Prague, Czech Republic.
“It confirmed that these enzymes play an important role in the severe degradation of corneal tissue leading to corneal perforation and loss of vision. Their involvement suggests that MMP inhibitors may play an important role in the treatment of this condition.”
Ms. Brejchova’s research, published online in November 2009 in Molecular Vision, gets specific, right down to the forms of MMP involved in melting, and recommends therapeutic solutions.

In detail

Ms. Brejchova analyzed one native melted cornea and 10 melted corneal grafts. MMPs were detected and examined using indirect enzyme immunohistochemistry, gelatin, and casein zymography. Controls included 11 normal corneas.
“In the melted specimens, stronger staining for MMP 9 was found in the epithelial fragments of all tested corneas [than in controls], if they were not destroyed,” Ms. Brejchova noted. “It was also found for MMP 1, 2, 3, and 7 in almost all melted corneas, compared to the controls.”
Some strong staining of MMPs even appeared in the endothelium or stroma of melted corneas.
Meanwhile, examination of the normal corneas revealed more superficial staining of MMPs, if at all. “No prominent differences in MMP staining were found among the individual control specimens for any of the MMPs tested,” Ms. Brejchova reported. “Moderate staining for MMP 1 and 2, and weak staining for MMP 8, were detected in the epithelium. A weak signal for MMP 2 was observed adjacent to Bowman’s layer, in approximately one-sixth of the anterior stroma. Weak staining was also found for MMP 1 and 8 in the endothelium of the control specimens. Immunostaining for MMP 3, 7, 9, and 13 was completely negative in all layers of all control corneas.”

What it all means

Some study results have been noted previously, such as a higher activity of MMP 1 and a high expression of MMP 9 in damaged corneal epithelium and stroma.
Other results are brand new. “Our study is the first to demonstrate the presence and activity of MMP 7 in melted corneas,” Ms. Brejchova reported. “Additionally, casein zymography showed a large quantity of inactive MMP 7 in all tested specimens and active MMP 7 in one specimen. We suggest that MMP 7 is an important element in the degradation of the corneal basement membrane in corneal melting, as it was abundant in the corneal epithelium, especially in its basal layer.”
Interestingly, different combinations of MMPs surfaced in different affected corneas. “This could have a number of causes, such as the different stages of melting at which the explants were obtained,” Ms. Brejchova noted. “It may also be that the expression of MMPs showed local variations within individual specimens, depending on the distance from the central melting point. It should be noted, however, that the staining and activity of individual MMPs were similar for consecutive sections obtained from each specimen.”
Ms. Brejchova appears to have no doubt that MMPs play a role in corneal disruption. “We hypothesize that in advanced cases of pSS, such as in our patients, MMPs may be upregulated to such an extent that the epithelial barrier is substantially degraded, followed by the dissolution of its basement membrane (caused mainly by MMP 3, 7, and 9) and the gradual degradation of the stroma, involving MMP 1, 3, 7, 8, and 9,” Ms. Brejchova noted. “After the stroma is completely lost, a descemetocele is formed, and finally the integrity of the whole cornea is disrupted.”
Treatment strategies including recombinant tissue inhibitors of MMPs and chemical inhibitors of MMPs should be considered, Ms. Brejchova suggested. “Direct inhibition of MMPs can be achieved by tetracyclines, medroxyprogesteron, or ion-chelating agents such as cysteine or thylenediaminetetraacetic acid,” Ms. Brejchova noted.
“Finally, an alternative approach in keratolysis treatment could be focused on the recovery and strengthening of the collagen structure by collagen cross-linking.”
Meanwhile, John D. Sheppard, M.D., professor of ophthalmology, microbiology, and immunology, Eastern Virginia Medical School, Norfolk, Va., agreed that MMPs have a critical role to play in the process of corneal dysfunction.
Already, he said, therapeutic strategies to inhibit MMPs are very good, and more are coming down the pipeline. “Systemic tetracycline has inhibited inflammatory degradation of ocular surface tissues for decades,” he said. But systemic doxycycline is his preferential treatment. Clinical trials of topical doxycycline are also underway to treat dry eye, Dr. Sheppard said.
“The accelerated cell turnover associated with MMPs is influential in patients with dry eye as well,” Dr. Sheppard said. Modification of normal cell turnover is what leads to a diseased corneal state, he said.
Topical azithromycin (AzaSite, Inspire Pharmaceuticals, Durham, N.C.) is another good option, Dr. Sheppard said. “Azithromycin is a very potent inhibitor of MMPs among other enzymes. A call for addressing MMP inhibition is a direct call for topical azithromycin.”

Editors’ note: Ms. Brejchova has no financial interests related to this study. Dr. Sheppard has financial interests with Inspire Pharmaceuticals (Durham, N.C.).

Contact information

Brejchova: 00 420 224 967 139, kjuklova@yahoo.com
Sheppard: 757-622-2203, jsheppard@vec2020.com