Roles of heparan sulfate sulfation in dentinogenesis

Satoru Hayano, Hiroshi Kurosaka, Takeshi Yanagita, Ina Kalus, Fabian Milz, Yoshihito Ishihara, Md Nurul Islam, Noriaki Kawanabe, Masahiro Saito, Hiroshi Kamioka, Taiji Adachi, Thomas Dierks, Takashi Yamashiro

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23 Citations (Scopus)

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 withHSsulfation 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.Wealso 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.

Original languageEnglish
Pages (from-to)12217-12229
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number15
DOIs
Publication statusPublished - Apr 6 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Hayano, S., Kurosaka, H., Yanagita, T., Kalus, I., Milz, F., Ishihara, Y., Islam, M. N., Kawanabe, N., Saito, M., Kamioka, H., Adachi, T., Dierks, T., & Yamashiro, T. (2012). Roles of heparan sulfate sulfation in dentinogenesis. Journal of Biological Chemistry, 287(15), 12217-12229. https://doi.org/10.1074/jbc.M111.332924