Jagged1 immobilization to an osteoconductive polymer activates the Notch signaling pathway and induces osteogenesis

Authors

  • Michael I. Dishowitz,

    1. Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Fengchang Zhu,

    1. Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Harini G. Sundararaghavan,

    1. Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Jamie L. Ifkovits,

    1. Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Jason A. Burdick,

    1. Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Kurt D. Hankenson

    Corresponding author
    1. Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    2. Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    • Correspondence to: K. D. Hankenson, Dean W. Richardson Chair in Equine Disease Research, Associate Professor of Equine Musculoskeletal Research and Orthopaedic Surgery, 311 Hill Pavilion, 380 S. University Ave., Philadelphia PA 19103, USA, e-mail: kdhank@vet.upenn.edu

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Abstract

Treatment of nonunion fractures is a significant problem. Common therapeutics, including autologous bone grafts and bone morphogenetic proteins, show well-established limitations. Therefore, a need persists for the identification of novel clinical therapies to promote healing. The Notch signaling pathway regulates bone development. Clinically, loss-of-function mutations to the Notch ligand Jagged1 decrease bone mass and increase fracture risk. Jagged1 is also the most highly upregulated ligand during fracture repair, identifying it as a potential target to promote bone formation. Therefore, the objective of this study was to develop a clinically translatable construct comprised of Jagged1 and an osteoconductive scaffold, and characterize its activity in human mesenchymal stem cells (hMSC). We first evaluated the effects of Jagged1 directly immobilized to a novel poly(β-amino ester) relative to indirect coupling via antibody. Direct was more effective at activating hMSC Notch target gene expression and osteogenic activity. We then found that directly immobilized Jagged1 constructs induced osteoblast differentiation. This is the first study to demonstrate that Jagged1 delivery transiently activates Notch signaling and increases osteogenesis. A positive correlation was found between Jagged1-induced Notch and osteogenic expression. Collectively, these results indicate that Jagged1 coupled to an osteogenic biomaterial could promote bone tissue formation during fracture healing. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 1558–1567, 2014.

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