Multiple Functions of Lysyl Oxidase Like-2 in Oral Fibroproliferative Processes

Abstract

Gingival overgrowth is a side effect of certain medications, including calcium channel blockers, cyclosporin A, and phenytoin. Phenytoin-induced gingival overgrowth is fibrotic. Lysyl oxidases are extracellular enzymes that are required for biosynthetic cross-linking of collagens, and members of this enzyme family are upregulated in fibrosis. Previous studies in humans and in a mouse model of phenytoin-induced gingival overgrowth have shown that LOXL2 is elevated in the epithelium and connective tissue in gingival overgrowth tissues and not in normal tissues. Here, using a novel LOXL2 isoform-selective inhibitor and knockdown studies in loss- and gain-of-function studies, we investigated roles for LOXL2 in promoting cultures of human gingival fibroblasts to proliferate and to accumulate collagen. Data indicate that LOXL2 stimulates gingival fibroblast proliferation, likely by a platelet-derived growth factor B receptor-mediated mechanism. Moreover, collagen accumulation was stimulated by LOXL2 enzyme and inhibited by LOXL2 inhibitor or gene knockdown. These studies suggest that LOXL2 could serve as a potential therapeutic target to address oral fibrotic conditions.