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Decreased EXT expression and intracellular accumulation of heparan sulphate proteoglycan in osteochondromas and

L Hameetman1, G David, A Yavas

  • 1Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.

The Journal of Pathology
|January 18, 2007
PubMed

Insights

Mutational inactivation of EXT1 or EXT2 genes causes hereditary multiple osteochondromas. This leads to decreased gene expression and intracellular accumulation of heparan sulphate proteoglycan core proteins in tumours.

Area of Science:

  • Genetics
  • Molecular Biology
  • Oncology

Background:

  • Hereditary multiple osteochondromas (HMO) result from mutations in EXT1 or EXT2 genes.
  • These genes are crucial for heparan sulphate proteoglycan (HSPG) biosynthesis within the Golgi apparatus.
  • Solitary osteochondromas often show loss of heterozygosity at the EXT1 locus, but somatic mutations are rare.

Purpose of the Study:

  • To investigate EXT1 and EXT2 gene expression and HSPG profiles in solitary and hereditary osteochondromas.
  • To correlate gene expression and HSPG changes with mutations and promoter methylation in osteochondromas and secondary chondrosarcomas.
  • To understand the molecular mechanisms underlying osteochondroma development and malignant progression.

Main Methods:

  • Quantitative RT-PCR was used to assess EXT1 and EXT2 mRNA expression.
  • Immunohistochemistry was employed to analyze the expression of various HSPGs.
  • Confocal microscopy was utilized to determine the subcellular localization of HSPGs.

Main Results:

  • Decreased EXT1 or EXT2 expression correlated with the mutation status in multiple osteochondromas.
  • No somatic point mutations or promoter hypermethylation were found in solitary osteochondromas, but 15 out of 17 showed reduced EXT1 expression.
  • Intracellular accumulation of syndecan-2 and CD44v3 was observed in most tumours, concentrating in the Golgi apparatus, unlike normal growth plates.

Conclusions:

  • Mutational inactivation of EXT1 or EXT2 directly leads to a loss of their respective mRNA expression.
  • Disruption of the EXT1/2 complex function in HSPG biosynthesis results in intracellular accumulation of HSPG core proteins.
  • This intracellular accumulation is a key feature in osteochondromas and may contribute to tumourigenesis.

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