Ultraviolet radiation and the role of matrix metalloproteinases in the pathogenesis of ocular surface squamous neoplasia.

PURPOSE Ocular surface squamous neoplasia (OSSN) is an uncommon tumor of the corneal and conjunctival epithelium associated with risk of permanent visual impairment. The purposes of this study were to (1) identify and localize potential mediators in tissue from patients with OSSN and (2) culture human dysplastic conjunctival epithelial cells (DCECs) to determine their responsiveness to ultraviolet (UV)-B radiation compared with normal conjunctival epithelial cells (NCECs). METHODS Immunohistochemical analysis was performed on OSSN (n = 23) and normal conjunctival (n = 17) tissue to identify matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Cell viability as well as basal and UVB-modulated levels of MMPs and TIMPs from DCECs and NCECs was determined by immunoassays, zymography, and RT-PCR. RESULTS A higher proportion of diseased specimens stained for MMP-1 (83%), MMP-3 (86%), TIMP-2 (87%), and TIMP-3 (83%) compared with normal conjunctiva (41%, 41%, 47%, and 53%, respectively). UVB radiation induced cell death and apoptosis at doses >/= 50 mJ/cm(2). MMP-1 and -3 mRNA and protein expression in DCECs was induced by UV and was mitogen-activated protein kinase-dependent, although the same enzymes were upregulated in NCECs only at doses that induced apoptosis. TIMP-1 and -2 levels remained relatively unchanged, except for a dose-dependent suppression of TIMP-3. CONCLUSIONS The results suggest that MMPs and TIMPs play a significant role in the pathogenesis of OSSN and that UVB initiates and perpetuates the development of this lesion on the ocular surface.