Niebler, Stephan and Schubert, Thomas and Hunziker, Ernst B. and Bosserhoff, Anja K. (2015) Activating enhancer binding protein 2 epsilon (AP-2 epsilon)-deficient mice exhibit increased matrix metalloproteinase 13 expression and progressive osteoarthritis development. ARTHRITIS RESEARCH & THERAPY, 17: 119. ISSN 1478-6354, 1478-6362
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Introduction: The transcription factor activating enhancer binding protein 2 epsilon (AP-2 epsilon) was recently shown to be expressed during chondrogenesis as well as in articular chondrocytes of humans and mice. Furthermore, expression of AP-2 epsilon was found to be upregulated in affected cartilage of patients with osteoarthritis (OA). Despite these findings, adult mice deficient for AP-2 epsilon (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-2 epsilon on skeletal development. In a second part, we aimed to define potential influences of AP-2 epsilon on articular cartilage function and gene expression, as well as on OA progression, in adult mice. Methods: Murine embryonic development was accessed via in situ hybridization, measurement of skeletal parameters and micromass differentiation of mesenchymal cells. To reveal discrepancies in articular cartilage of adult wild-type (WT) and Tfap2e(-/-) mice, light and electron microscopy, in vitro culture of cartilage explants, and quantification of gene expression via real-time PCR were performed. OA was induced via surgical destabilization of the medial meniscus in both genotypes, and disease progression was monitored on histological and molecular levels. Results: Only minor differences between WT and embryos deficient for AP-2 epsilon were observed, suggesting that redundancy mechanisms effectively compensate for the loss of AP-2 epsilon during skeletal development. Surprisingly, though, we found matrix metalloproteinase 13 (Mmp13), a major mediator of cartilage destruction, to be significantly upregulated in articular cartilage of adult Tfap2e(-/-) 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 Tfap2e(-/-) mice, which provided evidence for in vivo relevance. This finding is most likely attributable 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 with the WT. Conclusions: We reveal a novel role of AP-2 epsilon in the regulation of gene expression in articular chondrocytes, as well as in OA development, through modulation of Mmp13 expression and activity.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HUMAN COLLAGENASE-3 MMP-13; TRANSCRIPTION FACTOR; X COLLAGEN; ARTICULAR-CARTILAGE; CHONDROCYTE DIFFERENTIATION; GROWTH-PLATE; II-COLLAGEN; AP-2-EPSILON; CLONING; GENE; |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Jul 2019 09:13 |
| Last Modified: | 15 Jul 2019 09:13 |
| URI: | https://pred.uni-regensburg.de/id/eprint/5505 |
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