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    Synergism between Wnt3a and heparin enhances osteogenesis via a phosphoinositide 3-kinase/Akt/RUNX2 pathway

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    Authors
    Ling, Ling
    Dombrowski, Christian
    Foong, Kin Mun
    Haupt, Larisa M.
    Stein, Gary S.
    Nurcombe, Victor
    Van Wijnen, Andre J.
    Cool, Simon M.
    UMass Chan Affiliations
    Department of Cell Biology
    Document Type
    Journal Article
    Publication Date
    2010-08-16
    Keywords
    1-Phosphatidylinositol 4-Kinase
    Animals
    Cell Differentiation
    Cell Line
    Core Binding Factor Alpha 1 Subunit
    Drug Synergism
    Heparin
    Humans
    Mice
    Osteoblasts
    Osteogenesis
    Proto-Oncogene Proteins c-akt
    Signal Transduction
    Wnt Proteins
    Cell Biology
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    Link to Full Text
    http://dx.doi.org/10.1074/jbc.M110.122069
    Abstract
    A new strategy has emerged to improve healing of bone defects using exogenous glycosaminoglycans by increasing the effectiveness of bone-anabolic growth factors. Wnt ligands play an important role in bone formation. However, their functional interactions with heparan sulfate/heparin have only been investigated in non-osseous tissues. Our study now shows that the osteogenic activity of Wnt3a is cooperatively stimulated through physical interactions with exogenous heparin. N-Sulfation and to a lesser extent O-sulfation of heparin contribute to the physical binding and optimal co-stimulation of Wnt3a. Wnt3a-heparin signaling synergistically increases osteoblast differentiation with minimal effects on cell proliferation. Thus, heparin selectively reduces the effective dose of Wnt3a needed to elicit osteogenic, but not mitogenic responses. Mechanistically, Wnt3a-heparin signaling strongly activates the phosphoinositide 3-kinase/Akt pathway and requires the bone-related transcription factor RUNX2 to stimulate alkaline phosphatase activity, which parallels canonical beta-catenin signaling. Collectively, our findings establish the osteo-inductive potential of a heparin-mediated Wnt3a-phosphoinositide 3-kinase/Akt-RUNX2 signaling network and suggest that heparan sulfate supplementation may selectively reduce the therapeutic doses of peptide factors required to promote bone formation.
    Source
    J Biol Chem. 2010 Aug 20;285(34):26233-44. Epub 2010 Jun 14. Link to article on publisher's site
    DOI
    10.1074/jbc.M110.122069
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/49446
    PubMed ID
    20547765
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.M110.122069
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