Role of ocular matrix metalloproteinases in peripheral ulcerative keratitis

Aim-Peripheral ulcerative keratitis (PUK) is an ocular manifestation of rhe umatoid arthritis and other similar systemic diseases. The purpose of this inquiry was to investigate the involvement of matrix metalloproteinases (MM Ps) in the induction and/or maintenance of PUK. Methods-Substrate gel electrophoresis was used to characterise the MMP acti vities secreted by primary cultures of keratocytes derived from normal and perforated pathological corneal specimens, and those present in tears of no rmal 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 kerantocytes derived f rom perforated corneas of patients with PUK abnormally produce the PUK of a pparent M, 62 000. Other MMPs and in particular MMMP-9 of M-r 92 000, also occur in the tears of these patients. Their visualisation on substrate poly acrylamide gels correlated with clinical manifestations of disease activity ; during periods of disease quiescence they were barely detectable. The ste roid prednisolone, frequently used in systemic therapy, had no effect on th e in vitro activity of MMP-2, or on its production by cultured corneal kera tocytes. Although the in vitro activity of MMP-2 was inhibited by both Cu2 and Zn2+, Cu2+ apparently induced the keratocytes to produce activated enz yme and Zn2+ irreversibly inhibited their production of MMP-2. Conclusion-Overexpression of corneal MMP-2 and tear film MMP-9 are characte ristic 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 prod uction 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.