Role of ocular matrix metalloproteinases in peripheral ulcerative keratitis

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Abstract
AIM Peripheral ulcerative keratitis (PUK) is an ocular manifestation of rheumatoid arthritis and other similar systemic diseases. The purpose of this inquiry was to investigate the involvement of matrix metalloproteinases (MMPs) in the induction and/or maintenance of PUK. METHODS Substrate gel electrophoresis was used to characterise the MMP activities secreted by primary cultures of keratocytes derived from normal and perforated pathological corneal specimens, and those present in tears of normal subjects and patients with PUK. Substrate specificity and the in vivo activity status of the secreted MMPs was assessed by SDS-polyacrylamide gel electrophoresis of standard collagens incubated in the presence or absence of the various enzyme preparations. RESULTS In addition to MMP-2 of M r 66 000, cultured keratocytes derived from perforated corneas of patients with PUK abnormally produce the MMP-2 of apparentM r 62 000. Other MMPs and in particular MMP-9 of M r 92 000, also occur in the tears of these patients. Their visualisation on substrate polyacrylamide gels correlated with clinical manifestations of disease activity; during periods of disease quiescence they were barely detectable. The steroid prednisolone, frequently used in systemic therapy, had no effect on the in vitro activity of MMP-2, or on its production by cultured corneal keratocytes. Although the in vitro activity of MMP-2 was inhibited by both Cu2+ and Zn2+, Cu2+ apparently induced the keratocytes to produce activated enzyme and Zn2+ irreversibly inhibited their production of MMP-2. CONCLUSION Overexpression of corneal MMP-2 and tear film MMP-9 are characteristic features of patients with PUK and their activation may be a crucial facet of disease initiation or progression. Although effective in systemic therapy for PUK, prednisolone had no direct control over corneal MMP-2 production or activity. Zn2+ on the other hand inhibited both MMP-2 production and MMP-2 activity and may, therefore, be of therapeutic value if suitably formulated and used in conjunction with systemic steroid treatment.