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J. Biol. Chem., Vol. 280, Issue 36, 31353-31359, September 9, 2005

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BMP-2 and Insulin-like Growth Factor-I Mediate Osterix (Osx) Expression in Human Mesenchymal Stem Cells via the MAPK and Protein Kinase D Signaling Pathways^*

Ayse B. Celil and Phil G. Campbell¶

From the Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213 and the Institute for Complex Engineered Systems, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213

Genetic studies place the transcription factor Osterix (Osx) downstream of Runx2, but limited information is available about Osx regulation during osteoblastic differentiation. An important role for bone morphogenetic protein-2 (BMP-2) and insulin-like growth factor-I (IGF-I) on Osx expression and the requirement for p38 for the BMP-2-mediated effect was reported previously by our group. In this study, we continued to investigate the molecular mechanisms by which BMP-2 and IGF-1 regulate Osx expression during osteoblast lineage progression. IGF-I-mediated Osx expression required all three MAPK components (Erk, p38, and JNK), whereas BMP-2 required p38 and JNK signaling. As a common mediator of growth factor signaling, we also investigated the involvement of protein kinase C/D (PKC/D) signaling. BMP-2- and IGF-I-mediated Osx expression was blocked in response to a PKD inhibitor. A selective inhibitor of conventional PKCs had no effect on the BMP-2-mediated Osx expression. BMP-2 and IGF-I induced a selective phosphorylation of PKD, and PKD was required for mineralization. PKC/D and MAPK signaling also mediate Runx2 activity. Therefore, to document the implication for Runx2 in Osx regulation, we blocked Runx2 activity using a dominant negative Runx2 construct and an ubiquitination mediator for Runx2 degradation. We showed that blocking Runx2 activity inhibited the BMP-2-mediated induction of Osx. These studies implicated that multiple signaling pathways mediate Osx, a critical gene for osteoblast differentiation and bone formation. In addition to Runx2, other signaling components may be necessary to regulate Osx during osteoblast lineage progression.

Received for publication, April 8, 2005 , and in revised form, June 22, 2005.

^* This work was supported by a Pennsylvania Infrastructure Technology Alliance grant for Institute for Complex Engineered Systems (to P. G. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Institute for Complex Engineered Systems, Carnegie Mellon University, 5000 Forbes Ave., 1213 Hamburg Hall, Pittsburgh, PA 15213. Tel.: 412-268-4126; Fax: 412-268-5229; E-mail: pcampbel{at}cs.cmu.edu.

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