title: HSPG-deficient zebrafish uncovers dental aspect of multiple osteochondromas.
abstract: Multiple Osteochondromas (MO; previously known as multiple hereditary exostosis) is an autosomal dominant genetic condition that is characterized by the formation of cartilaginous bone tumours (osteochondromas) at multiple sites in the skeleton, secondary bursa formation and impingement of nerves, tendons and vessels, bone curving, and short stature. MO is also known to be associated with arthritis, general pain, scarring and occasional malignant transformation of osteochondroma into secondary peripheral chondrosarcoma. MO patients present additional complains but the relevance of those in relation to the syndromal background needs validation. Mutations in two enzymes that are required during heparan sulphate synthesis (EXT1 or EXT2) are known to cause MO. Previously, we have used zebrafish which harbour mutations in ext2 as a model for MO and shown that ext2⁻/⁻ fish have skeletal defects that resemble those seen in osteochondromas. Here we analyse dental defects present in ext2⁻/⁻ fish. Histological analysis reveals that ext2⁻/⁻ fish have very severe defects associated with the formation and the morphology of teeth. At 5 days post fertilization 100% of ext2⁻/⁻ fish have a single tooth at the end of the 5(th) pharyngeal arch, whereas wild-type fish develop three teeth, located in the middle of the pharyngeal arch. ext2⁻/⁻ teeth have abnormal morphology (they were shorter and thicker than in the WT) and patchy ossification at the tooth base. Deformities such as split crowns and enamel lesions were found in 20% of ext2⁺/⁻ adults. The tooth morphology in ext2⁻/⁻ was partially rescued by FGF8 administered locally (bead implants). Our findings from zebrafish model were validated in a dental survey that was conducted with assistance of the MHE Research Foundation. The presence of the malformed and/or displaced teeth with abnormal enamel was declared by half of the respondents indicating that MO might indeed be also associated with dental problems.
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Malgorzata I
authors.initials: MI
authors.lastname: Wiweger
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhao
authors.forename: Richard J P
authors.initials: RJ
authors.lastname: van Merkesteyn
authors.forename: Henry H
authors.initials: HH
authors.lastname: Roehl
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
mesh_terms: D000328:Adult; D000375:Aging / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D005097:Exostoses, Multiple Hereditary / Q000235:genetics / Q000473:pathology*; D018507:Gene Expression Regulation, Developmental; D019812:Heparan Sulfate Proteoglycans / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D007814:Larva; D009154:Mutation / Q000235:genetics; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D014070:Tooth / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D014076:Tooth Diseases / Q000235:genetics / Q000473:pathology*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D000099065:Exostosin 2
chemical_list: D015415:Biomarkers; D019812:Heparan Sulfate Proteoglycans; D017351:N-Acetylglucosaminyltransferases; D000099065:Exostosin 2