title: 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.
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
authors.forename: Ayse B
authors.initials: AB
authors.lastname: Celil
authors.forename: Jeffrey O
authors.initials: JO
authors.lastname: Hollinger
authors.forename: Phil G
authors.initials: PG
authors.lastname: Campbell
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins; D000076182:Sp7 Transcription Factor; D013234:Stem Cells / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D051785:Smad Proteins; D000076182:Sp7 Transcription Factor; C478163:SP7 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta