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J. Biol. Chem., Vol. 279, Issue 35, 37103-37114, August 27, 2004

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The Short Stature Homeodomain Protein SHOX Induces Cellular Growth Arrest and Apoptosis and Is Expressed in Human Growth Plate Chondrocytes^*

Antonio Marchini, Tiina Marttila, Anja Winter, Sandra Caldeira¶||, Ilaria Malanchi**, Rüdiger J. Blaschke, Beate Häcker, Ercole Rao, Marcel Karperien, Jan M. Wit, Wiltrud Richter, Massimo Tommasino**, and Gudrun A. Rappold¶¶

From the Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, Orthopaedic Hospital, University of Heidelberg, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany, the ^¶Institute of Molecular Medicine, University of Lisbon, 1649-028, Portugal, ^**Unit of Infection and Cancer, International Agency for Research on Cancer, World Health Organization, 150 Cours Albert Thomas, 69372, Lyon Cedex 08, France, and the Departments of Pediatrics and Endocrinology and Metabolic Diseases, Leiden University Medical Center, P. O. Box 9600, 2300 RC Leiden, The Netherlands

Mutations in the homeobox gene SHOX cause growth retardation and the skeletal abnormalities associated with Léri-Weill, Langer, and Turner syndromes. Little is known about the mechanism underlying these SHOX-related inherited disorders of bone formation. Here we demonstrate that SHOX expression in osteogenic stable cell lines, primary oral fibroblasts, and primary chondrocytes leads to cell cycle arrest and apoptosis. These events are associated with alterations in the expression of several cellular genes, including pRB, p53, and the cyclin kinase inhibitors p21^Cip1 and p27^Kip1. A SHOX mutant, such as seen in Léri-Weill syndrome patients, does not display these activities of the wild type protein. We have also shown that endogenous SHOX is mainly expressed in hypertrophic/apoptotic chondrocytes of the growth plate, strongly suggesting that the protein plays a direct role in regulating the differentiation of these cells. This study provides the first insight into the biological function of SHOX as regulator of cellular proliferation and viability and relates these cellular events to the phenotypic consequences of SHOX deficiency.

Received for publication, July 1, 2003 , and in revised form, May 14, 2004.

^* This work was supported by grants from Eli Lilly and Company, the Deutsche Forschungsgesellschaft, and the Medical Faculty of the University of Heidelberg. 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.

^|| Supported by Fundaçao para a Ciencia e Tecnologia.

^¶¶ To whom correspondence should be addressed. Tel.: 49-6221-565059; Fax: 49-6221-565332; E-mail: gudrun_rappold{at}med.uniheidelberg.de.

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