Activating enhancer binding protein 2 epsilon (AP-2ε)-deficient mice exhibit increased matrix metalloproteinase 13 expression and progressive osteoarthritis development

Stephan Niebler, Thomas Schubert, Ernst B Hunziker, Anja K Bosserhoff

The transcription factor activating enhancer-binding protein 2 epsilon (AP-2ε) was recently shown to be expressed during chondrogenesis as well as in articular chondrocytes of humans and mice. Further, expression of AP-2ε was found to be up-regulated in affected cartilage of osteoarthritis (OA) patients. Despite these findings, adult mice deficient for AP-2ε (Tfap2e-/-) do not exhibit an obviously abnormal cartilaginous phenotype. We therefore analyzed embryogenesis of Tfap2e-/- mice to elucidate potential transient abnormalities that provide information on the influence of AP-2ε on skeletal development. In a second part, we aimed to define potential influences of AP-2ε on articular cartilage function and gene expression as well as OA progression in adult mice. Murine embryonic development was accessed via in situ hybridization, measurement of skeletal parameters and micromass differentiation of mesenchymal cells. In order to reveal discrepancies in articular cartilage of adult wild type (WT) and Tfap2e -/- mice light and electron microscopy, in vitro culture of cartilage explants as well as quantification of gene expression via real-time PCR (polymerase chain reaction) was performed. Further, OA was induced via surgical destabilization of the medial meniscus in both genotypes and disease progression was monitored on histological and molecular levels. Only minor differences between WT and embryos deficient for AP-2ε were observed suggesting that redundancy mechanisms effectively compensate for the loss of AP-2ε during skeletal development. Surprisingly though, we found matrix metalloproteinase 13 (Mmp13), a major mediator of cartilage destruction, to be significantly up-regulated in articular cartilage of adult AP-2ε-deficient mice. This finding was further confirmed by increased Mmp13 activity and extracellular matrix degradation in Tfap2e -/- cartilage explants. OA progression was significantly enhanced in the AP-2ε-deficient mice, which provided evidence for in vivo relevance. Most likely, this finding is attributed to the increased basal Mmp13 expression level in Tfap2e-/- articular chondrocytes that results in a significantly higher total Mmp13 expression rate during OA as compared to the WT. Taken together, we revealed a novel role of AP-2ε in the regulation of gene expression in articular chondrocytes as well as osteoarthritis development through modulation of Mmp13 expression and activity.