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

Ling, L., Dombrowski, C., Foong, K. M., Haupt, Larisa 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), pp. 26233-26244.

View at publisher (open access)


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.

Impact and interest:

29 citations in Scopus
Search Google Scholar™
25 citations in Web of Science®

Citation counts are sourced monthly from Scopus and Web of Science® citation databases.

These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.

Citations counts from the Google Scholar™ indexing service can be viewed at the linked Google Scholar™ search.

ID Code: 69473
Item Type: Journal Article
Refereed: Yes
Additional Information: Articles free to read on journal website after 12 months
Additional URLs:
Keywords: 1-Phosphatidylinositol 4-Kinase/*metabolism, Animals, Cell Differentiation/drug effects, Cell Line, Core Binding Factor Alpha 1 Subunit/*metabolism, Drug Synergism, Heparin/*pharmacology, Humans, Mice, Osteoblasts/cytology/drug effects, Osteogenesis/*drug effects, Proto-Oncogene Proteins c-akt/*metabolism, Signal Transduction, Wnt Proteins/*pharmacology, Wnt3 Protein, Wnt3A Protein
DOI: 10.1074/jbc.M110.122069
ISSN: 1067-8816 (online) 0021-9258 (print)
Subjects: Australian and New Zealand Standard Research Classification > BIOLOGICAL SCIENCES (060000) > BIOCHEMISTRY AND CELL BIOLOGY (060100) > Cell Development Proliferation and Death (060103)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2010 The American Society for Biochemistry and Molecular Biology, Inc.
Deposited On: 06 Apr 2014 23:49
Last Modified: 04 Feb 2015 05:41

Export: EndNote | Dublin Core | BibTeX

Repository Staff Only: item control page