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Molecular and Cellular Biology, November 2005, p. 9460-9468, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9460-9468.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Loss of Smad3-Mediated Negative Regulation of Runx2 Activity Leads to an Alteration in Cell Fate Determination

Anita Borton Hjelmeland,1 Stephen H. Schilling,1 Xing Guo,1 Darryl Quarles,2 and Xiao-Fan Wang1*

Department of Pharmacology and Cancer Biology,1 Department of Nephrology, Duke University Medical Center, Durham, North Carolina 277102

Received 3 December 2004/ Returned for modification 28 December 2004/ Accepted 9 August 2005

Runx2 is required for osteoblast differentiation but is expressed in certain nonosteoblastic cells without activating the differentiation process, suggesting that its activity is suppressed through a lineage-specific mechanism. Here we report that primary mouse dermal fibroblasts lacking Smad3 can acquire an osteoblast-like phenotype, including activation of Runx2 activity, expression of osteoblast-specific genes, and calcium deposition. We further show that negative regulation of Runx2 activity by Smad3 in dermal fibroblasts is likely mediated by controlling the expression of Msx2, an antagonist of Runx2 in this cellular context. These data support the presence of a novel mechanism for controlling cell fate determination of mesenchymal lineages by preventing differentiation toward the osteoblastic lineage via negative regulation of Runx2 activity.

* Corresponding author. Mailing address: Department of Pharmacology & Cancer Biology, Duke University Medical Center, P.O. Box 3813, Durham, NC 27710. Phone: (919) 681-4861. Fax: (919) 681-7152. E-mail: wang0011{at}mc.duke.edu.

Molecular and Cellular Biology, November 2005, p. 9460-9468, Vol. 25, No. 21
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.21.9460-9468.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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