title: p38 MAP kinase is required for Wnt3a-mediated osterix expression independently of Wnt-LRP5/6-GSK3β signaling axis in dental follicle cells.
abstract: Wnt3a is a secreted glycoprotein that activates the glycogen synthase kinase-3β (GSK3β)/β-catenin signaling pathway through low-density-lipoprotein receptor-related protein (LRP)5/6 co-receptors. Wnt3a has been implicated in periodontal development and homeostasis, as well as in cementum formation. Recently, we have reported that Wnt3a increases alkaline phosphatase expression through the induction of osterix (Osx) expression in dental follicle cells, a precursor of cementoblasts. However, the molecular mechanism by which Wnt3a induces Osx expression is still unknown. In this study, we show that Wnt3a-induced Osx expression was inhibited in the presence of p38 mitogen-activated protein kinase (MAPK) inhibitors (SB203580 and SB202190) at gene and protein levels, as assessed by real-time PCR and immunocytohistochemistry, respectively. Pretreatment of cells with Dickkopf-1, a potent canonical Wnt antagonist binding to LRP5/6 co-receptors, did not influence Wnt3a-mediated p38 MAPK phosphorylation, suggesting that Wnt3a activates p38 MAPK through LRP5/6-independent signaling. On the other hand, pretreatment with p38 MAPK inhibitors had no effects on the phosphorylated status of GSK3β and β-catenin as well as β-catenin nuclear translocation, but inhibited Wnt3a-mediated β-catenin transcriptional activity. These findings suggest that p38 MAPK modulates canonical Wnt signaling at the β-catenin transcriptional level without any crosstalk with the Wnt3a-mediated LRP5/6-GSK3β signaling axis and subsequent β-catenin nuclear translocation. These findings expand our knowledge of the mechanisms controlling periodontal development and regeneration.
authors.affiliation: Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sakisaka
authors.affiliation: Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan; Liason Center for Innovative Dentistry, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Sousuke
authors.initials: S
authors.lastname: Kanaya
authors.affiliation: Department of Dental Pharmacology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Biochemistry and Molecular Biology, Hokkaido University Graduate School of Dentistry, Sapporo 060-8586, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Tamura
authors.affiliation: Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Shimauchi
authors.affiliation: Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan. Electronic address: e-nemoto@dent.tohoku.ac.jp.
authors.forename: Eiji
authors.initials: E
authors.lastname: Nemoto
mesh_terms: D000818:Animals; D002460:Cell Line; D003795:Dental Sac / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D060509:Wnt3A Protein / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D051153:Wnt Proteins; D060509:Wnt3A Protein; D000071679:Glycogen Synthase Kinase 3 beta; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Dental follicle cells; Osterix; Wnt3a; p38 MAPK; β-catenin