Heparan sulfate and the development of Exostoses

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Hereditary multiple exotoses syndrome (HME) is a dominant inherited human disorder characterized by short stature and exostoses (osteochondromas) of the growth plate. In up to 5% of patients these differentiate into chondrosarcomas. HME results from mutations in EXT1 or EXT2, which encode glycosyltransferases necessary for the synthesis of heparansulfate (HS). Investigation of hypomorphic Ext1 (Ext1gt/gt) mice demonstrated that reduced HS levels lead to an increased range of Ihh signaling and consequently to a delay in hypertrophic differentiation of chondrocytes. Here we aim to analyze the vascularization and ossification processes in these mutants, both of which are also disturbed. We will further investigate if other signaling systems are affected in Ext1gt/gt mutant bones. In parallel we will examine chimeric mice, in which clones of Ext1 mutant cells can be induced by Doxycyclinedependent exon inversions. Preliminary results indicate that, in contrast to heterozygous deletion of Ext1, these mice develop exostoses of the axial skeleton. Careful morphological analysis will identify the tissue in which the Exostoses originate. Molecular analysis and the generation of compound mutants should reveal if signaling of Ihh or other regulators of bone development are disturbed in the mutant clones or their environment. By single cell PCR we will identify the allelic status of the exostoses tissue and reveal if loss of heterozygosity is required for exostoses and or chondrosarcoma development. In the long run inhibition of the identified signaling pathway should help to develop possible treatment strategies. Together these studies will contribute to understand the molecular origin of HME.