AGE-induced keratinocyte MMP-9 expression is linked to TET2-mediated CpG demethylation

Studies have documented that unusually high expression of matrix metalloproteinase-9 (MMP-9) suppresses wound healing during the late stages of diabetic foot ulcers. Recently, it has been reported that the presence of advanced glycation end products-bovine serum albumin (AGE-BSA) resulted in a higher expression of MMP-9 in skin primary keratinocytes. The aim of the present study was to elucidate the molecular machinery that is responsible for the inappropriately high AGE-BSA-induced expression of MMP-9. It has been demonstrated that site-specific DNA demethylation played an important role in MMP-9 expression in AGE-BSA-stimulated keratinocytes. Ten-eleven translocation-2 (TET2) was up-regulated, whereas the percentage of methylation in the MMP-9 promoter was reduced. Furthermore, TET2 directly bound to a fragment surrounding the transcriptional start site in the MMP-9 promoter region, contributing to the regulation of MMP-9 expression. In addition, evidence indicated that TET2 affected the migration and proliferation in vitro of cultured skin primary keratinocytes. These findings indicated that TET2 directly interacted with the promoter region of MMP-9 in diabetic tissues and may be a novel master regulator of wound healing.