Differential Expression of Emmprin in Normal and Ulcerated Corneas: Role in Epithelio–Stromal Interactions and MMP Induction

Abstract

Abstract: : Purpose: Extracellular matrix metalloproteinase inducer (EMMPRIN) was originally identified on the tumor cell surface as an inducer of matrix metalloproteinases (MMPs) production in neighboring fibroblasts. Here we demonstrate a role for EMMPRIN in MMPs induction during corneal wound healing Methods: MMPs and EMMPRIN expression was analyzed in normal and ulcerated human corneas, as well as in corneal epithelial and stromal cells in culture using confoncal microscopy, zymography, immunoblots and real–time PCR Results: In normal cornea EMMPRIN was predominantly expressed in the epithelium but was markedly induced in the anterior stroma of ulcerated corneas. This coincided with MMP–2 induction which colocalized with EMMPRIN at the epithlio–stromal boundary. The role of epithelial–stromal interaction in MMP induction was investigated in an in–vitro coculture system and demonstrated an induction and colocalization of EMMPRIN and MMP–2 in the fibroblasts at the interface with epithelial cells. Direct contact of fibroblasts with EMMPRIN–containing purified epithelial cell membranes also induced MMP–1, MMP–2 and EMMPRIN and this was inhibited by a blocking anti–EMMPRIN antibody, suggesting that EMMPRIN was largely responsible for this induction Conclusions: In this study we demonstrate a role for EMMPRIN in wound healing and suggest that sustained local upregulation of EMMPRIN and MMPs in chronic situations where healing is delayed may lead to excessive matrix degradation and corneal melts.

Keywords: cornea: epithelium • wound healing • proteolysis