Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antimetabolites, Antineoplastic / pharmacology
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Apoptosis*
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Blotting, Western
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Body Height
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Bromodeoxyuridine / pharmacology
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Cell Cycle
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Cell Cycle Proteins / metabolism
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Cell Division
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Cell Line, Tumor
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Cell Separation
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Cells, Cultured
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Chondrocytes / metabolism*
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclins / metabolism
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Fibroblasts / metabolism
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Flow Cytometry
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Gene Deletion
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Growth Plate / metabolism*
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Homeodomain Proteins / chemistry
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Homeodomain Proteins / genetics*
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Homeodomain Proteins / physiology*
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Humans
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Immunohistochemistry
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In Situ Nick-End Labeling
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Mouth / metabolism
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Mutation*
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Protein Structure, Tertiary
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Retinoblastoma Protein / metabolism
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Retroviridae / genetics
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Short Stature Homeobox Protein
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Time Factors
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Transcription Factors / genetics*
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Transcription Factors / physiology*
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / metabolism
Substances
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Antimetabolites, Antineoplastic
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Homeodomain Proteins
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Retinoblastoma Protein
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SHOX protein, human
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Short Stature Homeobox Protein
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Transcription Factors
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Bromodeoxyuridine