Matrix metalloproteinase (MMP)-13 has a pivotal, rate-limiting function in cartilage remodeling and degradation due to its specificity for cleaving type II collagen. The proximal MMP13 promoter contains evolutionarily conserved E26 transformation-specific sequence binding sites that are closely flanked by AP-1 and Runx2 binding motifs, and interplay among these and other factors has been implicated in regulation by stress and inflammatory signals. Here we report that ELF3 directly controls MMP13 promoter activity by targeting an E26 transformation-specific sequence binding site at position ؊78 bp and by cooperating with AP-1. In addition, ELF3 binding to the proximal MMP13 promoter is enhanced by IL-1 stimulation in chondrocytes, and the IL-1-induced MMP13 expression is inhibited in primary human chondrocytes by siRNA-ELF3 knockdown and in chondrocytes from Elf3 ؊/؊ mice. Further, we found that MEK/ERK signaling enhances ELF3-driven MMP13 transactivation and is required for IL-1-induced ELF3 binding to the MMP13 promoter, as assessed by chromatin immunoprecipitation. Finally, we show that enhanced levels of ELF3 co-localize with MMP13 protein and activity in human osteoarthritic cartilage. These studies define a novel role for ELF3 as a procatabolic factor that may contribute to cartilage remodeling and degradation by regulating MMP13 gene transcription.The matrix metalloproteinases (MMPs) 3 are a family of enzymes that coordinately degrade components of the extracellular matrix in physiological/normal matrix remodeling processes (1) and in disease states wherein their aberrant and enhanced expression contributes to exacerbated matrix degradation (2, 3). Type II collagen is a major constituent of articular cartilage that contributes to its structural and functional properties by conferring tensile strength, and its degradation is the pivotal event that determines the irreversible progression of osteoarthritis (OA), in which articular cartilage is slowly and progressively destroyed (2). OA occurs in conjunction with changes in the synovium and subchondral bone that are associated with dysregulated chondrocyte physiology exemplified in part by the abnormal expression of catabolic and anabolic gene products (2). In this context, proinflammatory cytokines have been shown to trigger a diverse array of intracellular signaling pathways leading to the overexpression of a variety of matrix-degrading enzymes, including MMPs (2).Because collagen degradation is mediated almost exclusively by MMPs, those with higher collagenolytic activity (collagenases) are the rate-limiting, major players in irreversible cartilage destruction (4), and MMP13 (collagenase 3) plays a very prominent role here. MMP13 preferentially and more potently cleaves type II collagen compared with other collagenases (5-7). Moreover, MMP13 levels and activity are enhanced in OA cartilage, associated with degenerative changes and co-localizing with MMP13-specific type II collagen cleavage products, inflammatory cytokines, and their receptors (4,8). Furt...