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Genetic studies have revealed a critical role of Distal-homeobox (Dlx) genes in bone formation, and our previous study showed that  Dlx2  overexpressing in neural crest cells leads to profound abnormalities of the craniofacial tissues. The aim of this study was to investigate the role and the underlying molecular mechanisms of  Dlx2  in osteogenic differentiation of mouse bone marrow stromal cells (BMSCs) and pre-osteoblast MC3T3-E1 cells. Initially, we observed upregulation of Dlx2 during the early osteogenesis in BMSCs and MC3T3-E1 cells. Moreover,  Dlx2  overexpression enhanced alkaline phosphatase (ALP) activity and extracellular matrix mineralization in BMSCs and MC3T3-E1 cell line. In addition, micro-CT of implanted tissues in nude mice confirmed that  Dlx2  overexpression in BMSCs promoted bone formation in vivo. Unexpectedly,  Dlx2  overexpression had little impact on the expression level of the pivotal osteogenic transcription factors  Runx2 ,  Dlx5 ,  Msx2 , and  Osterix , but led to upregulation of  Alp  and  Osteocalcin  ( OCN ), both of which play critical roles in promoting osteoblast maturation. Importantly, luciferase analysis showed that  Dlx2  overexpression stimulated both  OCN  and  Alp  promoter activity. Through chromatin-immunoprecipitation assay and site-directed mutagenesis analysis, we provide molecular evidence that Dlx2 transactivates  OCN  and  Alp  expression by directly binding to the Dlx2-response  cis -acting elements in the promoter of the two genes. Based on these findings, we demonstrate that  Dlx2  overexpression enhances osteogenic differentiation in vitro and accelerates bone formation in vivo via direct upregulation of the  OCN  and  Alp  gene, suggesting that Dlx2 plays a crucial role in osteogenic differentiation and bone formation.

Overexpression of Dlx2 enhances osteogenic differentiation of BMSCs and MC3T3-E1 cells via direct upregulation of Osteocalcin and Alp