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

Abstract

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.

ACKNOWLEDGMENTS

We thank G. Karsenty for generously providing various constructs and Yong Yu for technical assistance.

This work was supported by grants DK064113 from the NIH and DAMD17-00-1-0230 from the U.S. Army Medical Research and Material Command at the Department of Defense. S.H.S. was a recipient of the NSF predoctoral fellowship and partially supported by grant T32 ES07031 from the NIH.