Downregulation of Wnt signaling by increased expression of Dickkopf-1 and -2 is a prerequisite for late-stage osteoblast differentiation of KS483 cells.
We examined the role of Wnt/beta-catenin signaling in successive stages of osteoblast differentiation. It has been shown that Wnt signaling in mature osteoblasts needs to be downregulated to enable the formation of a mineralized matrix. Using RNA interference, we showed that this is, at least in part, accomplished by upregulation of the Wnt antagonists Dickkopf-1 and -2. INTRODUCTION: The role of Wnt signaling in the initiation of osteoblast differentiation has been well studied. However, the role during late-stage differentiation is less clear. We have examined the role of Wnt/beta-catenin signaling in successive stages of osteoblast differentiation. MATERIALS AND METHODS: We treated murine bone marrow and mesenchymal stem cell-like KS483 cells with either LiCl or Wnt3A during several stages of osteoblast differentiation. In addition, we generated stable KS483 cell lines silencing either the Wnt antagonist Dkk-1 or -2 RESULTS: Activation of Wnt signaling by LiCl inhibits the formation of a mineralized bone matrix in both cell types. Whereas undifferentiated KS483 cells respond to Wnt3A by inducing nuclear beta-catenin translocation, differentiated cells do not. This is at least in part accomplished by upregulated expression of Dkk-1 and -2 during osteoblast differentiation. Using RNA interference, we showed that Dkk-1 plays a crucial role in blunting the BMP- induced alkaline phosphatase ( ALP) response and in the transition of an ALP+ osteoblast in a mineralizing cell. In contrast, Dkk-2 plays a role in osteoblast proliferation and the initiation of osteoblast differentiation. CONCLUSIONS: Our data suggest that Wnt signaling in maturing osteoblasts needs to be downregulated to enable the formation of a mineralized bone matrix. Furthermore, they suggest that Dkk-1 and Dkk-2 may have distinct functions in osteoblast differentiation.[1]References
- Downregulation of Wnt signaling by increased expression of Dickkopf-1 and -2 is a prerequisite for late-stage osteoblast differentiation of KS483 cells. van der Horst, G., van der Werf, S.M., Farih-Sips, H., van Bezooijen, R.L., Löwik, C.W., Karperien, M. J. Bone Miner. Res. (2005) [Pubmed]
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