AP-1 and Cbfa/Runt Physically Interact and Regulate Parathyroid Hormone-dependent MMP13 Expression in Osteoblasts through a New Osteoblast-specific Element 2/AP-1 Composite Element

• DOI: 10.1074/jbc.m010601200
• Publication Date: 2002-07-26T15:09:24Z
• Authors: Jochen Hess; Dominique Porte; Christine Munz; Peter Angel
• Keywords: Leucine Zippers; 0303 health sciences; Osteoblasts; Base Sequence; Proto-Oncogene Proteins c-jun; Core Binding Factor Alpha 1 Subunit; Recombinant Proteins; Cell Line; Neoplasm Proteins; Transcription Factor AP-1; Mice; 03 medical and health sciences; Parathyroid Hormone; Matrix Metalloproteinase 13; Animals; Humans; Tetradecanoylphorbol Acetate; Collagenases; Proto-Oncogene Proteins c-fos; DNA Primers; Protein Binding; Transcription Factors

The expression of MMP13 (collagenase-3), a member of the matrix metalloproteinase family, is increased in vivo as well as in cultured osteosarcoma cell lines by parathyroid hormone (PTH), a major regulator of calcium homeostasis. Binding sites for AP-1 and Cbfa/Runt transcription factors in close proximity have been identified as cis-acting elements in the murine and rat mmp13 promoter required for PTH-induced expression. The cooperative function of these factors in response to PTH in osteoblastic cells suggests a direct interaction between AP-1 and Cbfa/Runt transcription factors. Here, we demonstrate interaction between c-Jun and c-Fos with Cbfa/Runt proteins. This interaction depends on the leucine zipper of c-Jun or c-Fos and the Runt domain of Cbfa/Runt proteins, respectively. Moreover, c-Fos interacts with the C-terminal part of Cbfa1 and Cbfa2, sharing a conserved transcriptional repression domain. In addition to the distal osteoblast-specific element 2 (OSE2) element in the murine and rat mmp13 promoter, we identified a new proximal OSE2 site overlapping with the TRE motif. Both interaction of Cbfa/Runt proteins with AP-1 and the presence of a functional proximal OSE2 site are required for enhanced transcriptional activity of the mmp13 promoter in transient transfected fibroblasts and in PTH-treated osteosarcoma cells.