An association between Wnt/beta-catenin signaling and MMP13 expression has been reported but there has been little information about the underlying mechanism. Here, we investigated the role of Lef1 in IL-I P-mediated MMP13 regulation in mouse chondrocytes. Lef1 and beta-catenin synergistically upregulated MMPI 3 transcription while knock-down of Lef1 using Lef1 siRNA downregulated IL-1 beta-mediated MMP13 expression. Lef1 binding site was mapped to the 3' region of the MMP13 genomic locus and binding of Lef1/beta-catenin to the site was confirmed by chromatin immunoprecipitation (ChlP) assays and electrophoretic mobility shift assays (EMSAs). Furthermore, Lef1/beta-catenin binding to the Lef1 binding site transactivated MMP13 promoter activity. Our results suggest a pivotal role of Lef1/beta-catenin in MMP13 regulation in chondrocytes, which might be associated with matrix loss of degenerated arthritic cartilage. (C) 2007 Elsevier Inc. All rights reserved.