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

Ling Ling, Christian Dombrowski, Kin Mun Foong, Larisa M. Haupt, Gary S. Stein, Victor Nurcombe, Andre J. Van Wijnen, Simon M. Cool

Research output: Contribution to journalArticle

45 Scopus citations

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 β-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.

Original languageEnglish (US)
Pages (from-to)26233-26244
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number34
DOIs
StatePublished - Aug 20 2010

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Ling, L., Dombrowski, C., Foong, K. M., Haupt, L. M., Stein, G. S., Nurcombe, V., Van Wijnen, A. J., & Cool, S. M. (2010). Synergism between Wnt3a and heparin enhances osteogenesis via a phosphoinositide 3-kinase/Akt/RUNX2 pathway. Journal of Biological Chemistry, 285(34), 26233-26244. https://doi.org/10.1074/jbc.M110.122069