PKCδ Is Required for Jagged-1 Induction of Human Mesenchymal Stem Cell Osteogenic Differentiation§

Authors

  • Fengchang Zhu,

    1. Department of Clinical Studies-New Bolton Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    2. Department of Animal Biology, School of Veterinary Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Mariya T. Sweetwyne,

    1. Department of Clinical Studies-New Bolton Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    2. Department of Animal Biology, School of Veterinary Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Kurt D. Hankenson

    Corresponding author
    1. Department of Clinical Studies-New Bolton Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    2. Department of Animal Biology, School of Veterinary Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    3. Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    • Dean W. Richardson Chair in Equine Disease Research, Associate Professor of Musculoskeletal Research and Orthopaedic Surgery, 311 Hill Pavilion, 380 S. University Ave., Philadelphia, Pennsylvania 19104, USA
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    • Telephone: 215-746-1873; Fax: 215-746-2295


  • Author contributions: F.Z.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; M.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; K.H.: conception and design, financial support, data analysis and interpretation, manuscript writing, and final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    first published online in STEM CELLS EXPRESS December 29, 2012.

Abstract

JAG1, the gene for the Jagged-1 ligand (Jag1) in the Notch signaling pathway, is variably mutated in Alagille Syndrome (ALGS). ALGS patients have skeletal defects, and additionally JAG1 has been shown to be associated with low bone mass through genome-wide association studies. Plating human osteoblast precursors (human mesenchymal stem cells—hMSCs) on Jag1 is sufficient to induce osteoblast differentiation; however, exposure of mouse MSC (mMSC) to Jag1 actually inhibits osteoblastogenesis. Overexpression of the notch-2 intracellular domain (NICD2) is sufficient to mimic the effect of Jag1 on hMSC osteoblastogenesis, while blocking Notch signaling with a γ-secretase inhibitor or with dominant-negative mastermind inhibits Jag1-induced hMSC osteoblastogenesis. In pursuit of interacting signaling pathways, we discovered that treatment with a protein kinase C δ (PKCδ) inhibitor abrogates Jag1-induced hMSC osteoblastogenesis. Jag1 results in rapid PKCδ nuclear translocation and kinase activation. Furthermore, Jag1 stimulates the physical interaction of PKCδ with NICD. Collectively, these results suggest that Jag1 induces hMSC osteoblast differentiation through canonical Notch signaling and requires concomitant PKCδ signaling. This research also demonstrates potential deficiencies in using mouse models to study ALGS bone abnormalities. STEM Cells 2013;31:1181–1192

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