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    A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses

    Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10932-7. Epub 2010 Jun 1.

    In this paper the authors examine a mouse model of the human disease multiple hereditary exostoses, which produces multiple cartilage-capped bony protrusions called osteochondromas. They find that the lesions develop in their model with somatic inactivation of the Ext1 gene. This result suggests that loss of heterozygosity is involved in the development of this condition in patients. In addition, the authors show that the lesions are composed of both mutant and normal chondrocytes, which suggests that some interaction of the mutant and normal cells is necessary for the development of the disease.

    Authors: Matsumoto K, Irie F, Mackem S, et. al

    Multiple hereditary exostoses (MHE) is one of the most common skeletal dysplasias, exhibiting the formation of multiple cartilage-capped bony protrusions (osteochondroma) and characteristic bone deformities. Individuals with MHE carry heterozygous loss-of-function mutations in Ext1 or Ext2, genes which together encode an enzyme essential for heparan sulfate synthesis. Despite the identification of causative genes, the pathogenesis of MHE remains unclear, especially with regard to whether osteochondroma results from loss of heterozygosity of the Ext genes. Hampering elucidation of the pathogenic mechanism of MHE, both Ext1(+/-) and Ext2(+/-) heterozygous mutant mice, which mimic the genetic status of human MHE, are highly resistant to osteochondroma formation, especially in long bones. To address these issues, we created a mouse model in which Ext1 is stochastically inactivated in a chondrocyte-specific manner. We show that these mice develop multiple osteochondromas and characteristic bone deformities in a pattern and a frequency that are almost identical to those of human MHE, suggesting a role for Ext1 LOH in MHE. Surprisingly, however, genotyping and fate mapping analyses reveal that chondrocytes constituting osteochondromas are mixtures of mutant and wild-type cells. Moreover, osteochondromas do not possess many typical neoplastic properties. Together, our results suggest that inactivation of Ext1 in a small fraction of chondrocytes is sufficient for the development of osteochondromas and other skeletal defects associated with MHE. Because the observed osteochondromas in our mouse model do not arise from clonal growth of chondrocytes, they cannot be considered true neoplasms.

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