Distal-less 3 (DLX3) is a highly conserved homeobox containing transcription factor. DLX3 is specifically expressed in osteoblasts and osteocytes of all developing bones. DLX3 is essential for osteoblast differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. Akt can be activated by several osteogenic signaling molecules, but its precise function and downstream targets in bone development are unknown. In this report, we investigated a potential regulation of Dlx3 function by Akt1. We found that Akt1 phosphorylates Dlx3 and Akt1 activation increases protein stability, osteogenic activity and transcriptional activity of Dlx3. Also, BMP2 was shown to increase the protein level of Dlx3 in an Akt1 activity-dependent manner. Conversely, inhibition of Akt1 by the Akt inhibitor decreases the protein levels of Dlx3. These results suggest that Dlx3 is a novel target of Akt1 and the activity of Dlx3 could be modulated by a novel mechanism involving Akt1 during osteoblast differentiation. (C) 2012 Elsevier Inc. All rights reserved.