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Both AP-1 and Cbfa1-like factors are required for the induction of interstitial collagenase by parathyroid hormone

Oncogene volume 18, pages 667–678 (1999)Cite this article

Abstract

PTH is a major regulator of calcium homeostasis by mobilizing calcium through bone resorption. We show that the expression of collagenase-3 (MMP-13), a member of the family of matrix metalloproteinases, required for the cleavage of collagens in the bone, is increased upon PTH injection in mice. A cis-acting element in the collagenase-3 promoter was identified which, together with AP-1, is required for induction by PTH. This element contains CCACA motifs which are required for binding of the 65 kDa osteoblast-specific splice variant of Cbfa1. Introduction of mutations in this binding site that interfere with protein interaction also eliminates PTH inducibilty and transactivation by Cbfa/Runt proteins. While DNA binding activity of AP-1 is increased upon PTH treatment, high basal level of Cbfa/Runt binding activity is detectable in untreated cells which is not further increased by PTH, suggesting that AP-1 and Cbfa1 contribute to transcriptional activation through different mechanisms. In agreement with the critical role of both proteins defined in tissue culture cells, expression of collagenase-3 is reduced in mice lacking c-fos and is completely absent in cbfa1−/− embryos. These data provide the first evidence for a critical role of Cbfa1, a major regulator of bone development, in PTH-dependent processes such as bone resorption.

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Acknowledgements

We thank NC Partridge for sharing unpublished data on the rat MMP-13 promoter and for the rat cDNA library from osteosarcoma cells, S Gack for initial analysis of c-fos−/− embryos, and EF Wagner for c-fos knockout mice. We are grateful to N Keon for critical reading of the manuscript and to I Herr for help in performing UV cross-linking analysis. This work was supported by grants from the Deutsche Forschungsgemeinschaft (An 182/6-2) and the Training and Mobility of Researchers Programme of the European Community (ERBFMBICT961818), and by a PhD fellowship from the Boehringer Ingelheim Fonds.

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Author notes

  1. D Porte, J Tuckermann, M Becker and P Angel: D Porte, J Tuckermann and M Becker contributed equally to this work

Authors and Affiliations

  1. Abteilung Signaltransduktion und Wachstumskontrolle, Deutsches Krebsforschungszentrum, D-69120, Heidelberg, Germany

    D Porte, J Tuckermann, M Becker, B Baumann, S Teurich, M Schorpp-Kistner & P Angel

  2. Forschungszentrum Karlsruhe, Institut für Genetik, D-76021, Karlsruhe, Germany

    M Becker

  3. Imperial Cancer Research Fund, Lincoln's Inn Fields, London, WC2A 3PX

    T Higgins & M J Owen

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  1. D Porte
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Porte, D., Tuckermann, J., Becker, M. et al. Both AP-1 and Cbfa1-like factors are required for the induction of interstitial collagenase by parathyroid hormone. Oncogene 18, 667–678 (1999). https://doi.org/10.1038/sj.onc.1202333

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