Osx transcriptional regulation is mediated by additional pathways to BMP2/Smad signaling

Abstract

Bone morphogenetic protein (BMP)-2 induces Osterix (Osx) in mouse C2C12 cells and chondrocytes. Genetic studies place Osx downstream to the BMP-2/Smad/Runx2 signaling pathway; however, limited information is available on the mediators of Osx expression in osteoblast lineage commitment. Several lines of research implicate the presence of Runx2-independent ossification. Therefore, the purpose of this study was to identify possible mediators of Osx expression beyond the BMP-2/Smad pathway. Using real-time RT-PCR, we showed upregulation of Osx in response to BMP-2 in human mesenchymal stem cells (hMSC). Insulin-like growth factor (IGF)-I upregulated Osx, but not Runx2. Further, IGF-I in combination with BMP-2 was synergistic for Osx, suggesting a pathway beyond Smad signaling. MAPK was tested as a common mediator across BMP-2 and IGF-I signaling pathways. Inhibition of MAPK component ERK1/2 did not affect Runx2 gene expression, but inhibited Osx expression and matrix mineralization. BMP-2-mediated Osx expression was downregulated in response to p38 inhibition. We therefore conclude that during osteogenic lineage progression, in addition to the BMP-2/Smad pathway, IGF-I and MAPK signaling may mediate Osx.