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One-day treatment of small molecule 8-bromo-cyclic AMP analogue induces cell-based VEGF production for in vitro angiogenesis and osteoblastic differentiation

Authors

  • Kevin W.-H. Lo,

    Corresponding author
    1. Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA
    2. Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA
    3. Department of Medicine, Division of Endocrinolog, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA
    4. Department of Biomedical Engineering, University of Connecticut, School of Engineering, Storrs, CT, USA
    • Correspondence to: Kevin W.-H. Lo, Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, USA. E-mail: wlo@uchc.edu

      Cato T. Laurencin, Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, USA. E-mail: laurencin@uchc.edu

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  • Ho Man Kan,

    1. Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA
    2. Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA
    3. Department of Orthopedic Surgery, School of Medicine, University of Connecticut Health Center, Farmington, CT, USA
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  • Keith A. Gagnon,

    1. Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA
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  • Cato T. Laurencin

    1. Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA
    2. Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA
    3. Department of Biomedical Engineering, University of Connecticut, School of Engineering, Storrs, CT, USA
    4. Department of Orthopedic Surgery, School of Medicine, University of Connecticut Health Center, Farmington, CT, USA
    5. Department of Chemical, Materials and Biomolecular Engineering, University of Connecticut, School of Engineering, Storrs, CT, USA
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Abstract

Small molecule-based regenerative engineering is emerging as a promising strategy for regenerating bone tissue. Small molecule cAMP analogues have been proposed as novel biofactors for bone repair and regeneration and, while promising, the effect that these small molecules have on angiogenesis, a critical requirement for successful bone regeneration, is still unclear. Our previous research demonstrated that the small molecule cAMP analogue 8-bromoadenosine-3′,5′-cyclic monophosphate (8-Br-cAMP) was able to promote initial osteoblast adhesion on a polymeric scaffold via cAMP signalling cascades. Here, we report that 8-Br-cAMP is capable of inducing in vitro cell-based VEGF production for angiogenesis promotion. We first demonstrated that treating osteoblast-like MC3T3-E1 cells with 8-Br-cAMP for 1 day significantly increased VEGF production and secretion. We then demonstrated that 8-Br-cAMP-induced cell-secreted VEGF is biologically active and may promote angiogenesis, as evidenced by increased human umbilical vein endothelial cells (HUVECs) migration and tubule formation. In addition, treatment of MC3T3-E1 cells with 8-Br-cAMP for as short as a single day resulted in enhanced ALP activity as well as matrix mineralization, demonstrating in vitro osteoblastic differentiation. A short-term 8-Br-cAMP treatment also addresses the concern of non-specific cytotoxicity, as our data indicate that a 1-day 8-Br-cAMP treatment scheme supports cellular proliferation of MC3T3-E1 cells as well as HUVECs. While the major concern associated with small molecule drugs is the risk of non-specific cytotoxicity, the short exposure treatment outlined in this paper provides a very promising strategy to mitigate the risk associated with small molecules. Copyright © 2013 John Wiley & Sons, Ltd.

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