Canonical Wnts and BMPs cooperatively induce osteoblastic differentiation through a GSK3β-dependent and β-catenin-independent mechanism

• DOI: 10.1016/j.diff.2010.05.002
• Publication Date: 2010-05-25T08:21:40Z
• Authors: Toru Fukuda; Shoichiro Kokabu; Satoshi Ohte; Hiroki Sasanuma; Kazuhiro Kanomata; Katsumi Yoneyama; Hitoshi Kato; Masumi Akita; Hiromi Oda; Takenobu Katagiri
• Keywords: 0303 health sciences; Glycogen Synthase Kinase 3 beta; Osteoblasts; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Cell Differentiation; Alkaline Phosphatase; Smad1 Protein; Myoblasts; Wnt Proteins; Glycogen Synthase Kinase 3; Mice; 03 medical and health sciences; Bone Morphogenetic Proteins; Animals; RNA, Messenger; Luciferases; Cells, Cultured; beta Catenin; Signal Transduction

Both BMPs and Wnts play important roles in the regulation of bone formation. We examined the molecular mechanism regulating cross-talk between BMPs and Wnts in the osteoblastic differentiation of C2C12 cells. Canonical Wnts (Wnt1 and Wnt3a) but not non-canonical Wnts (Wnt5a and Wnt11) synergistically stimulated ALP activity in the presence of BMP-4. Wnt3a and BMP-4 synergistically stimulated the expression of type I collagen and osteonectin. However, Wnt3a did not stimulate ALP activity that was induced by a constitutively active BMP receptor or Smad1. Noggin and Dkk-1 suppressed the synergistic effect of BMP-4 and Wnt3a, but Smad7 did not. Overexpression of beta-catenin did not affect BMP-4-induced ALP activity. By contrast, inhibition or stimulation of GSK3beta activity resulted in either stimulation or suppression of ALP activity, respectively, in the presence of BMP-4. Taken together, these findings suggest that BMPs and canonical Wnts may regulate osteoblastic differentiation, especially at the early stages, through a GSK3beta-dependent but beta-catenin-independent mechanism.