Loss of Smad3-mediated negative regulation of Runx2 activity leads to an alteration in cell fate determination.
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.
Hjelmeland
Anita Borton
AB
Department of Pharmacology & Cancer Biology, Duke University Medical Center, P.O. Box 3813, Durham, NC 27710, USA.
Schilling
Stephen H
SH
Guo
Xing
X
Quarles
Darryl
D
Wang
Xiao-Fan
XF
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D012867:Skin / Q000166:cytology / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*
D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C084119:MSX2 protein; C493716:Runx2 protein, mouse; D051900:Smad3 Protein