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Regenerative dental therapies for bone tissues rely on efficient targeting of endogenous and transplanted mesenchymal stem cells (MSCs) to guide bone formation. Amelogenin is the primary component of Emdogain, which is used to regenerate periodontal defects; however, the mechanisms underlying the therapeutic effects on alveolar bone remain unclear. The tetracycline (Tet)-dependent transcriptional regulatory system is a good candidate to investigate distinct roles of genes of interest during stem cell differentiation. Here, we investigated amelogenin-dependent regulation of osteogenesis in MSCs by establishing a Tet-controlled transcriptional activation system. Clonal mouse bone marrow-derived MSCs were lentivirally transduced with the Tet repressor (TetR) expression vector followed by drug selection to obtain MSCs constitutively expressing  TetR  (MSCs- TetR ). Expression vectors that contained the Tet operator and amelogenin-coding ( Amelx ) cDNA fragments were constructed using the Gateway system and lentivirally introduced into MSCs- TetR  to generate a Tet regulation system in MSCs (MSCs- TetR / Amelx ). MSCs- TetR / Amelx  significantly overexpressed the  Amelx  gene and protein in the presence of the tetracycline derivative doxycycline. Concomitant expression of  osterix ,  bone sialoprotein  ( BSP ),  osteopontin , and  osteocalcin  was modulated by addition or removal of doxycycline under osteogenic guidance. During osteogenic induction, MSCs- TetR / Amelx  treated with doxycycline showed significantly increased gene expression of  osterix ,  type I collage n,  BSP , and  osteocalcin  in addition to increased alkaline phosphatase activity and mineralized nodule formation. Enhanced extracellular matrix calcification was observed when forced  Amelx  expression commenced at the early stage but not at the intermediate or late stages of osteogenesis. These results suggest that a Tet-controlled  Amelx  gene regulation system for mouse MSCs was successfully established, in which transcriptional activation of  Amelx  was associated with enhanced osteogenic differentiation, especially in the early stage of biomineralization.

Controlled Osteogenic Differentiation of Mouse Mesenchymal Stem Cells by Tetracycline-Controlled Transcriptional Activation of Amelogenin