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dc.contributor.authorLing, Ling
dc.contributor.authorDombrowski, Christian
dc.contributor.authorFoong, Kin Mun
dc.contributor.authorHaupt, Larisa M.
dc.contributor.authorStein, Gary S.
dc.contributor.authorNurcombe, Victor
dc.contributor.authorVan Wijnen, Andre J.
dc.contributor.authorCool, Simon M.
dc.date2022-08-11T08:10:56.000
dc.date.accessioned2022-08-23T17:25:37Z
dc.date.available2022-08-23T17:25:37Z
dc.date.issued2010-08-16
dc.date.submitted2011-01-11
dc.identifier.citationJ Biol Chem. 2010 Aug 20;285(34):26233-44. Epub 2010 Jun 14. <a href="http://dx.doi.org/10.1074/jbc.M110.122069">Link to article on publisher's site</a>
dc.identifier.issn0021-9258 (Linking)
dc.identifier.doi10.1074/jbc.M110.122069
dc.identifier.pmid20547765
dc.identifier.urihttp://hdl.handle.net/20.500.14038/49446
dc.description.abstractA 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=20547765&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1074/jbc.M110.122069
dc.subject1-Phosphatidylinositol 4-Kinase
dc.subjectAnimals
dc.subjectCell Differentiation
dc.subjectCell Line
dc.subjectCore Binding Factor Alpha 1 Subunit
dc.subjectDrug Synergism
dc.subjectHeparin
dc.subjectHumans
dc.subjectMice
dc.subjectOsteoblasts
dc.subjectOsteogenesis
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectSignal Transduction
dc.subjectWnt Proteins
dc.subjectCell Biology
dc.titleSynergism between Wnt3a and heparin enhances osteogenesis via a phosphoinositide 3-kinase/Akt/RUNX2 pathway
dc.typeJournal Article
dc.source.journaltitleThe Journal of biological chemistry
dc.source.volume285
dc.source.issue34
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/stein/10
dc.identifier.contextkey1724050
html.description.abstract<p>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.</p>
dc.identifier.submissionpathstein/10
dc.contributor.departmentDepartment of Cell Biology
dc.source.pages26233-44


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