title: Bone morphogenetic protein-2 modulates Wnt and frizzled expression and enhances the canonical pathway of Wnt signaling in normal keratinocytes.
abstract: BACKGROUND
  Bone morphogenetic protein-2 (BMP-2) and Wnt are involved in the normal development and tumorigenesis of several organs, and in the development of skin and skin appendages as a morphogen. However, the crosstalk between BMP-2 and the Wnt/beta-catenin signaling pathway is not clear.
  
  
  OBJECTIVE
  We examined BMP-2-dependent expression of Wnt and its receptor frizzled in normal human keratinocytes.
  
  
  METHODS
  The mRNA expression of the Wnt and frizzled families was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) or ribonuclease protection assay. beta-Catenin expression was measured using RT-PCR and Western blotting. T-cell factor/lymphoid enhancing factor activity was analyzed using the luciferase reporter assay.
  
  
  RESULTS
  We detected the expression of Wnt-2b/13, -4, -5a, -5b, -7a, -7b, and -10a, frizzled-1, -4, -5, -6, -8, -9, and -10, MFRP, and SFRP-1/SARP-2 in keratinocytes. BMP-2 increased Wnt-2b/13, -5b, and -7b, and frizzled-6, -8, and -10. Conversely, BMP-2 suppressed Wnt-10a and SFRP-1/SARP-2. Although Wnt-4 expression was not affected by BMP-2 in confluent conditioned keratinocytes, BMP-2 suppressed cell density-dependent Wnt-4 induction. The transcriptional activity of TCF/LEF, which is a target of the canonical Wnt pathway, was upregulated by BMP-2 in both time- and dose-dependent manners. However, BMP-2-dependent differentiation of keratinocytes suppressed TCF/LEF transcriptional activity.
  
  
  CONCLUSIONS
  These results suggest that BMP-2 modulates the expression of molecules involved in Wnt signaling, and activates the canonical Wnt pathway in normal human keratinocytes. Moreover, Wnt signaling may be influenced by the fate of keratinocytes, such as proliferation, migration, and differentiation.
authors.affiliation: Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
authors.forename: Lujun
authors.initials: L
authors.lastname: Yang
authors.forename: Kenshi
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shirakata
authors.forename: Xiuju
authors.initials: X
authors.lastname: Dai
authors.forename: Sho
authors.initials: S
authors.lastname: Tokumaru
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yahata
authors.forename: Mikiko
authors.initials: M
authors.lastname: Tohyama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hanakawa
authors.forename: Koji
authors.initials: K
authors.lastname: Sayama
authors.forename: Koji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002478:Cells, Cultured; D051157:Frizzled Receptors; D005786:Gene Expression Regulation; D006801:Humans; D007223:Infant; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D017981:Receptors, Neurotransmitter / Q000096:biosynthesis*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*; D051153:Wnt Proteins / Q000096:biosynthesis*; D060528:Wnt4 Protein
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; C489740:FZD1 protein, human; D051157:Frizzled Receptors; D011518:Proto-Oncogene Proteins; D017981:Receptors, Neurotransmitter; D016212:Transforming Growth Factor beta; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein