title: Roles of heparan sulfate sulfation in dentinogenesis.
abstract: Cell surface heparan sulfate (HS) is an essential regulator of cell signaling and development. HS traps signaling molecules, like Wnt in the glycosaminoglycan side chains of HS proteoglycans (HSPGs), and regulates their functions. Endosulfatases Sulf1 and Sulf2 are secreted at the cell surface to selectively remove 6-O-sulfate groups from HSPGs, thereby modifying the affinity of cell surface HSPGs for its ligands. This study provides molecular evidence for the functional roles of HSPG sulfation and desulfation in dentinogenesis. We show that odontogenic cells are highly sulfated on the cell surface and become desulfated during their differentiation to odontoblasts, which produce tooth dentin. Sulf1/Sulf2 double null mutant mice exhibit a thin dentin matrix and short roots combined with reduced expression of dentin sialophosphoprotein (Dspp) mRNA, encoding a dentin-specific extracellular matrix precursor protein, whereas single Sulf mutants do not show such defective phenotypes. In odontoblast cell lines, Dspp mRNA expression is potentiated by the activation of the Wnt canonical signaling pathway. In addition, pharmacological interference with HS sulfation promotes Dspp mRNA expression through activation of Wnt signaling. On the contrary, the silencing of Sulf suppresses the Wnt signaling pathway and subsequently Dspp mRNA expression. We also show that Wnt10a protein binds to cell surface HSPGs in odontoblasts, and interference with HS sulfation decreases the binding affinity of Wnt10a for HSPGs, which facilitates the binding of Wnt10a to its receptor and potentiates the Wnt signaling pathway, thereby up-regulating Dspp mRNA expression. These results demonstrate that Sulf-mediated desulfation of cellular HSPGs is an important modification that is critical for the activation of the Wnt signaling in odontoblasts and for production of the dentin matrix.
authors.affiliation: Department of Orthodontics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Hayano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kurosaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yanagita
authors.forename: Ina
authors.initials: I
authors.lastname: Kalus
authors.forename: Fabian
authors.initials: F
authors.lastname: Milz
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Ishihara
authors.forename: Md Nurul
authors.initials: MN
authors.lastname: Islam
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kawanabe
authors.forename: Masahiro
authors.initials: M
authors.lastname: Saito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kamioka
authors.forename: Taiji
authors.initials: T
authors.lastname: Adachi
authors.forename: Thomas
authors.initials: T
authors.lastname: Dierks
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamashiro
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003804:Dentin / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D003810:Dentinogenesis; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008963:Molar / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009804:Odontoblasts / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D013429:Sulfatases / Q000235:genetics / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D014071:Tooth Abnormalities / Q000201:enzymology / Q000235:genetics; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D060449:Wnt Signaling Pathway; D000099311:Dentin Sialophosphoprotein
chemical_list: D016326:Extracellular Matrix Proteins; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D012795:Sialoglycoproteins; D013429:Sulfatases; D015238:Sulfotransferases; D051153:Wnt Proteins; D000099311:Dentin Sialophosphoprotein; C484143:Wnt10a protein, mouse; C486773:Sulf1 protein, mouse; C514911:Sulf2 protein, mouse