title: The molecular and cellular basis of exostosis formation in hereditary multiple exostoses.
abstract: The different clinical entities of osteochondromas, hereditary multiple exostoses (HME) and non-familial solitary exostosis, are known to express localized exostoses in their joint metaphyseal cartilage. In the current study biopsies of osteochondromas patients were screened with respect to a number of cellular and molecular parameters. Specifically, cartilaginous biopsy samples of nine HME patients, 10 solitary exostosis patients and 10 articular cartilages of control subjects were collected and cell cultures were established. Results obtained showed that one of the two HME samples that underwent DNA sequencing analysis (HME-1) had a novel mutation for an early stop codon, which led to an aberrant protein, migrating at a lower molecular weight position. The EXT-1 mRNA and protein levels in chondrocyte cultures derived from all nine HME patients were elevated, compared with solitary exostosis patients or control subjects. Furthermore, cell cultures of HME patients had significantly decreased pericellular heparan sulphate (HS) in comparison with cultures of solitary exostosis patients or control subjects. Immunohistochemical staining of tissue sections and Western blotting of cell cultures derived from HME patients revealed higher levels of heparanase compared with solitary exostosis patients and of control subjects. Further investigations are needed to determine whether the low pericellular HS levels in HME patients stem from decreased biosynthesis of HS, increased degradation or a combination of both. In conclusion, it appears that due to a mutated glycosyltransferase, the low content of pericellular HS in HME patients leads to the anatomical deformations with exostoses formation. Hence, elevation of HS content in the pericellular regions should be a potential molecular target for correction.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.
authors.forename: Meirav
authors.initials: M
authors.lastname: Trebicz-Geffen
authors.forename: Dror
authors.initials: D
authors.lastname: Robinson
authors.forename: Zoharia
authors.initials: Z
authors.lastname: Evron
authors.forename: Tova
authors.initials: T
authors.lastname: Glaser
authors.forename: Mati
authors.initials: M
authors.lastname: Fridkin
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Kollander
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.forename: Kit Fong
authors.initials: KF
authors.lastname: Law
authors.forename: Kathryn S E
authors.initials: KS
authors.lastname: Cheah
authors.forename: Danny
authors.initials: D
authors.lastname: Chan
authors.forename: Haim
authors.initials: H
authors.lastname: Werner
authors.forename: Zvi
authors.initials: Z
authors.lastname: Nevo
mesh_terms: D000918:Antibody Specificity; D001483:Base Sequence; D016022:Case-Control Studies; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D004252:DNA Mutational Analysis; D005096:Exostoses / Q000235:genetics* / Q000473:pathology; D005097:Exostoses, Multiple Hereditary / Q000235:genetics*; D015870:Gene Expression; D005966:Glucuronidase / Q000032:analysis / Q000235:genetics; D006025:Glycosaminoglycans / Q000032:analysis / Q000235:genetics; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D017351:N-Acetylglucosaminyltransferases / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000099058:Exostosin 1; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D006025:Glycosaminoglycans; D017351:N-Acetylglucosaminyltransferases; D012333:RNA, Messenger; D000099058:Exostosin 1; D000099175:Heparanase