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Molecular Regulation of Osteoactivin Expression in Osteoblasts

Osteoblast (OB) commitment, proliferation and differentiation from mesenchymal stem cells are regulated by Bone Morphogenetic Protein2 (BMP2). BMP2 mediates these osteoinductive effects by recruiting Transcription Factors (TFs), namely Runx2, Homeodomain (HD), Smad1 and Smad4 proteins to the promoter of OB specific genes and induces their transcription. Our laboratory has previously shown that Osteoactivin (OA), OB‐related glycoprotein acts as a downstream mediator of BMP2 effects on OB differentiation and function. Furthermore, we showed that Smad1 signaling regulates BMP2 induced OA expression. The goal of our study is to characterize OB specific TFs that regulate BMP2 induced OA promoter activity. In order to study the effects of BMP2 on OA promoter activity, we cloned 1kb upstream of rat OA gene into a luciferase expression vector and have shown that BMP2 stimulates OA promoter activity in a time and dose‐dependent manner. Secondly, knockdown of Runx2, HD, Smad1 and Smad4 using specific siRNAs decreased BMP2 induced OA promoter activity. Similarly, loss of consensus binding sites of these TFs from OA promoter decreased OA promoter activity. Furthermore, ChiP assays at various stages of OB differentiation indicated that Runx2, Smad1, Smad4 and HD proteins associate differentially with OA promoter. Collectively, our results suggest that Runx2, Smad1, Smad4 and HD TFs differentially regulate BMP2 induced OA promoter activity during OB differentiation.