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J. Biol. Chem., Vol. 281, Issue 42, 31790-31800, October 20, 2006

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Twisted Gastrulation Modulates Bone Morphogenetic Protein-induced Collagen II and X Expression in Chondrocytes in Vitro and in Vivo^*

Martina Schmidl¹, Nadia Adam¹, Cordula Surmann-Schmitt¹, Takako Hattori², Michael Stock, Uwe Dietz, Benoit de Crombrugghe, Ernst Pöschl³, and Klaus von der Mark⁴

From the Department of Experimental Medicine I, Nikolaus-Fiebiger Center of Molecular Medicine, University of Erlangen-Nuremberg, 91054 Erlangen, Germany and Department of Molecular Genetics, M. D. Anderson Cancer Center, University of Texas, Houston, Texas 77030

Twisted gastrulation (TSG) is an extracellular modulator of bone morphogenetic protein (BMP) activity and regulates dorsoventral axis formation in early Drosophila and Xenopus development. Studies on tsg-deficient mice also indicated a role of this protein in skeletal growth, but the mechanism of TSG activity in this process has not yet been investigated. Here we show for the first time by in situ hybridization and immunohistochemistry that TSG is strongly expressed in bovine and mouse growth plate cartilage as well as in fetal ribs, vertebral cartilage, and cartilage anlagen of the skull. Furthermore we provide evidence that TSG is directly involved in BMP-regulated chondrocyte differentiation and maturation. In vitro, TSG impaired the dose-dependent BMP-2 stimulation of collagen II and X expression in cultures of MC615 chondrocytes and primary mouse chondrocytes. In the presence of chordin, a BMP antagonist, the inhibitory effect of TSG was further enhanced. TSG also inhibited BMP-2-stimulated phosphorylation of Smad factors in chondrocytes, confirming the role of TSG as a modulator of BMP signaling. For analysis of TSG functions in cartilage development in vivo, the gene was overexpressed in transgenic mice under the control of the cartilage-specific Col2a1 promoter. As a result, Col10a1 expression was significantly reduced in the growth plates of transgenic embryos and newborns in comparison with wild type littermates as shown by in situ hybridization and by real time PCR analysis. The data suggest that TSG is an important modulator of BMP-regulated cartilage development and chondrocyte differentiation.

Received for publication, April 10, 2006 , and in revised form, July 10, 2006.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant Ma-534-18/1 (to K. v. d. M.) and National Institutes of Health Grant PO1 AR042919 (to B. d. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Present address: Dept. of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan.

³ Present address: University of East Anglia, School of Biological Sciences, Norwich NR4 7TJ, UK.

⁴ To whom correspondence should be addressed: Dept. of Experimental Medicine I, Nikolaus-Fiebiger Center of Molecular Medicine, University of Erlangen-Nuremberg, Glueckstr. 6, 91054 Erlangen, Germany. Fax: 49-9131-8526341; E-mail: kvdmark{at}molmed.uni-erlangen.de.

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