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J. Biol. Chem., Vol. 279, Issue 51, 53323-53330, December 17, 2004

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Phosphophoryn Regulates the Gene Expression and Differentiation of NIH3T3, MC3T3-E1, and Human Mesenchymal Stem Cells via the Integrin/MAPK Signaling Pathway^*

Julie Jadlowiec, Hannjörg Koch, Xiaoyuan Zhang¶, Phil G. Campbell||, Merriam Seyedain¶, and Charles Sfeir¶**

From the ^¶Department of Oral Medicine and Pathology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 and the Department of Biological Sciences, the Bone Tissue Engineering Center, and the ^||Institute for Complex Engineered Systems, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213

Extracellular matrix proteins (ECMs) serve as both a structural support for cells and a dynamic biochemical network that directs cellular activities. ECM proteins such as those of the SIBLING family (small integrin-binding ligand glycoprotein) could possess inherent growth factor activity. In this study, we demonstrate that exon 5 of dentin matrix protein 3 (phosphophoryn (PP)), a non-collagenous dentin ECM protein and SIBLING protein family member, up-regulates osteoblast marker genes in primary human adult mesenchymal stem cells (hMSCs), a mouse osteoblastic cell line (MC3T3-E1), and a mouse fibroblastic cell line (NIH3T3). Quantitative real-time PCR technology was used to quantify gene expression levels of bone markers such as Runx2, Osx (Osterix), bone/liver/kidney Alp (alkaline phosphatase), Ocn (osteocalcin), and Bsp (bone sialoprotein) in response to recombinant PP and stably transfected PP. PP up-regulated Runx2, Osx, and Ocn gene expression. PP increased OCN protein production in hMSCs and MC3T3-E1. ALP activity and calcium deposition was increased by PP in hMSC. Furthermore, an _v3 integrin-blocking antibody significantly inhibited recombinant PP-induced expression of Runx2 in hMSCs, suggesting that signaling by PP is mediated through the integrin pathway. PP was also shown to activate p38, ERK1/2, and JNK, three components of the MAPK pathway. These data demonstrate a novel signaling function for PP in cell differentiation beyond the hypothesized role of PP in biomineralization.

Received for publication, May 4, 2004 , and in revised form, August 24, 2004.

^* Funding for this work was provided by grants from the University of Pittsburgh Central Research Development Fund (to C. S.), the Scaife Foundation (to P. G. C.), and the Pennsylvania Infrastructure Technology Alliance (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: Dept. of Oral Medicine and Pathology, University of Pittsburgh, 693A Salk Hall, 3501 Terrace St., Pittsburgh, PA 15261-1964; Tel.: 412-648-1949; E-mail: csfeir{at}pitt.edu.

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