Osterix (Osx) is a novel zinc finger-containing transcription factor that is essential for osteoblast differentiation and bone formation in bone homeostasis. The mitogen-activated protein (MAP) kinases are a group of evolutionarily conserved proline-directed protein serine/threonine kinases that are activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. Erk1/2 plays essential roles in osteoblast differentiation and in supporting osteoclastogenesis, but the precise molecular signaling mechanisms between Osterix and Erk1/2 are not known. We therefore focused on the relationship between Osterix and Erk1/2 during osteoblast differentiation because BMP signaling induces Erk activation in osteoblasts. We investigated the role of the MAPK pathway in regulating protein levels and transcriptional functions of Osterix. We found that Erk activation by overexpression of constitutively active MEK increased the mRNA and protein levels of Osterix and enhanced the transcriptional activity of Osterix, whereas U0126, an inhibitor of MEK, suppressed the protein levels of Osterix and the transcriptional activity. Also, overexpression of constitutively active MEK stabilized Osterix protein. These results suggest that Erk1/2 regulates a major transcription factor, Osterix, during osteoblast differentiation by increasing its protein stability and transcriptional activity. (C) 2011 Elsevier Inc. All rights reserved.