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J. Biol. Chem., Vol. 279, Issue 18, 19327-19334, April 30, 2004

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Transforming Growth Factor-1 Regulation of Collagenase-3 Expression in Osteoblastic Cells by Cross-talk between the Smad and MAPK Signaling Pathways and Their Components, Smad2 and Runx2^*

Nagarajan Selvamurugan, Sukyee Kwok, Tamara Alliston¶, Michael Reiss||, and Nicola C. Partridge

From the Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, the ^¶Department of Growth and Development, University of California, San Francisco, California 94143, and the ^||Department of Medicine, Cancer Institute of New Jersey, New Brunswick, New Jersey 08903

Transforming growth factor- (TGF-) plays a key role in osteoblast differentiation and bone development and remodeling. Collagenase-3 (matrix metalloproteinase-13) is expressed by osteoblasts and seems to be involved in osteoclastic bone resorption. Here, we show that TGF-1 stimulates collagenase-3 expression in the rat osteoblastic cell line UMR 106-01 and requires de novo protein synthesis. Dominant-negative Smad2/3 constructs indicated that Smad signaling is essential for TGF-1-stimulated collagenase-3 promoter activity. Inhibitors of the ERK1/2 and p38 MAPK pathways, but not the JNK pathway, reduced TGF-1-stimulated collagenase-3 expression, indicating that the p38 MAPK and ERK1/2 pathways are also required for TGF-1-stimulated collagenase-3 expression in UMR 106-01 cells. These inhibitors did not prevent nuclear localization of Smad proteins, but they inhibited Smad-mediated transcriptional activation. We have shown for the first time that Runx2 (a bone transcription factor and a potential substrate for the MAPK pathway) is phosphorylated in response to TGF-1 treatment in osteoblastic cells. Cotransfection of Smad2 and Runx2 constructs had a cooperative effect on TGF-1-stimulated collagenase-3 promoter activity in these cells. We further identified ligand-independent physical interaction between Smad2 and Runx2. Taken together, our results provide an important role for cross-talk between the Smad and MAPK pathways and their components in expression of collagenase-3 following TGF-1 treatment in UMR 106-01 cells.

Received for publication, December 22, 2003 , and in revised form, February 17, 2004.

^* This work was supported by grants from the New Jersey Commission on Cancer Research, the Foundation for the University of Medicine and Dentistry of New Jersey (to N. S.), and the National Institutes of Health Grant DK47420 (to N. C. P.) and by Grant DAMD17-01-1-0656 from the Department of Defense, United States Army (to N. S.). 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 Physiology and Biophysics, UMDNJ-RWJMS, 675 Hoes Lane, Piscataway, NJ 08854. Tel.: 732-235-2821; Fax: 732-235-5038; E-mail: selvamn2{at}umdnj.edu.

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