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J. Biol. Chem., Vol. 280, Issue 31, 28572-28580, August 5, 2005

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Gene Disruption of Spred-2 Causes Dwarfism^*

Karin Bundschu, Klaus-Peter Knobeloch¶, Melanie Ullrich, Thorsten Schinke||, Michael Amling||, Catherine M. Engelhardt, Thomas Renné, Ulrich Walter, and Kai Schuh**

From the Institut für Klinische Biochemie und Pathobiochemie, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany, the Universitäts-Frauenklinik, Josef-Schneider-Strasse 4, 97080 Würzburg, Germany, the ^¶Forschungsinstitut für Molekulare Pharmakologie, Krahmerstrasse 6, 12207 Berlin, Germany, and the ^||Experimentelle Unfallchirurgie, Martinistrasse 52, 20246 Hamburg, Germany

The impact of the fibroblast growth factor receptor 3 (FGFR3)-mediated signaling pathway on bone growth has been demonstrated by various genetic approaches. Overexpression of fibroblast growth factors (FGFs), several gain-of-function mutations in the FGFR3, and constitutive activation of mitogen-activated protein kinase (MAPK) kinase (MEK1) in chondrocytes have been shown to cause dwarfism in mice by activation of the MAPK signaling pathway. To investigate the previously reported inhibitory role of Spred in the FGFR3/MAPK pathway, we generated mice with a trapped Spred-2 gene. Here we show that lack of functional Spred-2 protein in mice caused a dwarf phenotype, similar to achondroplasia, the most common form of human dwarfism. Spred-2^-/- mice showed reduced growth and body weight, they had a shorter tibia length, and showed narrower growth plates as compared with wild-type mice. We detected promoter activity and protein expression of Spred-2 in chondrocytes, suggesting an important function of Spred-2 in chondrocytes and bone development. Stimulation of chondrocytes with different FGF concentrations showed earlier and augmented ERK phosphorylation in Spred-2^-/- chondrocytes in comparison to Spred-2^+/+ chondrocytes. Our observations suggest a model in which loss of Spred-2 inhibits bone growth by inhibiting chondrocyte differentiation through up-regulation of the MAPK signaling pathway.

Received for publication, April 4, 2005 , and in revised form, June 9, 2005.

^* This work was supported by grants of the Interdisziplinäres Zentrum für Klinische Forschung Wuerzburg (to K. B.), the German Research Foundation (Deutsche Forschungsgemeinschaft), Novartis-Foundation, Germany, and the Deutsche Vereinigte Gesellschaft für Klinische Chemie und Laboratoriumsmedizin "DGKL Scherer-Stipendium" (to K. B.). 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.

^** To whom correspondence should be addressed: Institut für Klinische Biochemie und Pathobiochemie, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany. Tel.: 49-931-201-36116; Fax: 49-931-201-45137; E-mail: kai.schuh{at}klin-biochem.uni-wuerzburg.de.

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