Downregulation of ErbB3 by Wnt3a contributes to wnt-induced osteoblast differentiation in mesenchymal cells.

Mesenchymal stem cells (MSC) can differentiate into osteoblasts upon activation of Wnt signaling. Identifying targets of Wnt signaling in MSC may help promote MSC osteoblast differentiation for bone regeneration. In this study, using microarray analysis we found that Wnt3a upregulates neuregulin 1 (NRG-1) during Wnt3a-induced osteoblast differentiation in primary human MSC and murine C3H10T1/2 mesenchymal cells. Western blot and qPCR analyses confirmed that NRG-1 is upregulated by Wnt3a, and that this effect was counterbalanced by decreased expression of the NRG-1 receptor ErbB3. Consistently, exogenous NRG-1 had no effect on alkaline phosphatase (ALP) activity, an early marker of osteoblast differentiation. In contrast, small interfering RNA-mediated silencing of endogenous NRG-1 increased basal and Wnt3a-induced ALP activity in MSC. We showed that short hairpin (sh) ErbB3 and Wnt3a additively increased β-catenin transcriptional activity and ALP activity in MSC. These effects were abrogated by DKK1, indicating that cross-talk between Wnt3a and ErbB3 control MSC osteoblast differentiation via Wnt/β-catenin signaling. Furthermore, ErbB3 silencing decreased Src expression. Pharmacological inhibition of Src signaling promoted ErbB3- and Wnt-induced ALP activity, suggestive of a role of Src signaling in the modulation of osteoblast differentiation by ErbB3 and Wnt3a. The results indicate that downregulation of ErbB3 induced by Wnt3a contributes to Wnt3a-induced early osteoblast differentiation of MSCs through increased canonical Wnt/β-catenin signaling and decreased Src signaling.

Jullien N ，Maudinet A ，Leloutre B ，Ringe J ，Häupl T ，Marie PJ ... -  《-》

Dkk1-induced inhibition of Wnt signaling in osteoblast differentiation is an underlying mechanism of bone loss in multiple myeloma.

Qiang YW ，Barlogie B ，Rudikoff S ，Shaughnessy JD Jr ... -  《-》

FHL2 mediates dexamethasone-induced mesenchymal cell differentiation into osteoblasts by activating Wnt/beta-catenin signaling-dependent Runx2 expression.

Hamidouche Z ，Haÿ E ，Vaudin P ，Charbord P ，Schüle R ，Marie PJ ，Fromigué O ... -  《-》

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 SM ，Farih-Sips H ，van Bezooijen RL ，Löwik CW ，Karperien M ... -  《JOURNAL OF BONE AND MINERAL RESEARCH》

The role of the Wnt/β-catenin pathway in the effect of implant topography on MG63 differentiation.

Wnt/β-catenin signaling plays a key role in bone formation. To assess the role of this signaling cascade in the response of osteoblasts to the implant topography, human MG63 osteoblasts are cultured on micropitted/nanotubular surface topographies (MNTs) and the transcriptional expressions of Wnt/β-catenin pathway receptors, activators, and inhibitors are measured. β-catenin signaling and cell differentiation are studied in the absence and presence of exogenous Dickkopf 1 (Dkk1) on the MNTs and exogenous Wnt3a on a smooth surface. The expressions of the Wnt/β-catenin pathway receptor low-density lipoprotein receptor-related protein 6 and pathway ligand Wnt3a are up-regulated by the MNTs whereas those of the pathway inhibitors including Dkk1/2 and secreted frizzled-related protein 1/2 are down-regulated by the MNTs, indicating regulation of the Wnt/β-catenin pathway modulators to activate the pathway. Consequently, the β-catenin signaling activity is enhanced by the MNTs as well as cell differentiation in terms of osteogenesis-related gene expressions and alkaline phosphatase and collagen products. On the smooth surface, exogenous Wnt3a stimulates β-catenin signaling and cell differentiation while exogenous Dkk1 attenuates the enhancement by the MNTs. The results explicitly demonstrate that the implant topography regulates the product of the Wnt/β-catenin pathway modulators from the cells and in turn activates the cell Wnt/β-catenin pathway promoting osteoblast differentiation.

Wang W ，Zhao L ，Ma Q ，Wang Q ，Chu PK ，Zhang Y ... -  《-》