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Article: Beta-catenin signaling plays a disparate role in different phases of fracture repair: Implications for therapy to improve bone healing

TitleBeta-catenin signaling plays a disparate role in different phases of fracture repair: Implications for therapy to improve bone healing
Authors
KeywordsAllele
Animal Experiment
Animal Model
Animal Tissue
Article
Cartilage
Controlled Study
Fracture Healing
Fracture Nonunion
Fracture Treatment
Male
Mouse
Nonhuman
Null Allele
Ossification
Osteoblast
Protein Expression
Regulatory Mechanism
Reporter Gene
Reverse Transcription Polymerase Chain Reaction
Signal Transduction
Tibia Fracture
Tissue Repair
Transcription Regulation
Transgenic Mouse
Upregulation
Western Blotting
Issue Date2007
PublisherPublic Library of Science. The Journal's web site is located at http://medicine.plosjournals.org/perlserv/?request=index-html&issn=1549-1676
Citation
PLoS Medicine, 2007, v. 4 n. 7, p. 1216-1229 How to Cite?
AbstractBackground: Delayed fracture healing causes substantial disability and usually requires additional surgical treatments. Pharmacologic management to improve fracture repair would substantially improve patient outcome. The signaling pathways regulating bone healing are beginning to be unraveled, and they provide clues into pharmacologic management. The β-catenin signaling pathway, which activates T cell factor (TCF)-dependent transcription, has emerged as a key regulator in embryonic skeletogenesis, positively regulating osteoblasts. However, its role in bone repair is unknown. The goal of this study was to explore the role of β-catenin signaling in bone repair. Methods and Findings: Western blot analysis showed significant up-regulation of β-catenin during the bone healing process. Using a β-Gal activity assay to observe activation during healing of tibia fractures in a transgenic mouse model expressing a TCF reporter, we found that β-catenin-mediated, TCF-dependent transcription was activated in both bone and cartilage formation during fracture repair. Using reverse transcription-PCR, we observed that several WNT ligands were expressed during fracture repair. Treatment with DKK1 (an antagonist of WNT/β-catenin pathway) inhibited β-catenin signaling and the healing process, suggesting that WNT ligands regulate β-catenin. Healing was significantly repressed in mice conditionally expressing either null or stabilized β-catenin alleles induced by an adenovirus expressing Cre recombinase. Fracture repair was also inhibited in mice expressing osteoblast-specific β-catenin null alleles. In stark contrast, there was dramatically enhanced bone healing in mice expressing an activated form of β-catenin, whose expression was restricted to osteoblasts. Treating mice with lithium activated β-catenin in the healing fracture, but healing was enhanced only when treatment was started subsequent to the fracture. Conclusions: These results demonstrate that β-catenin functions differently at different stages of fracture repair. In early stages, precise regulation of β-catenin is required for pluripotent mesenchymal cells to differentiate to either osteoblasts or chondrocytes. Once these undifferentiated cells have become committed to the osteoblast lineage, β-catenin positively regulates osteoblasts. This is a different function for β-catenin than has previously been reported during development. Activation of β-catenin by lithium treatment has potential to improve fracture healing, but only when utilized in later phases of repair, after mesenchymal cells have become committed to the osteoblast lineage. © 2007 Chen et al.
Persistent Identifierhttp://hdl.handle.net/10722/92206
ISSN
2011 Impact Factor: 16.269
2015 SCImago Journal Rankings: 5.667
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorChen, Yen_HK
dc.contributor.authorWhetstone, HCen_HK
dc.contributor.authorLin, ACen_HK
dc.contributor.authorNadesan, Pen_HK
dc.contributor.authorWei, Qen_HK
dc.contributor.authorPoon, Ren_HK
dc.contributor.authorAlman, BAen_HK
dc.date.accessioned2010-09-17T10:39:12Z-
dc.date.available2010-09-17T10:39:12Z-
dc.date.issued2007en_HK
dc.identifier.citationPLoS Medicine, 2007, v. 4 n. 7, p. 1216-1229en_HK
dc.identifier.issn1549-1277en_HK
dc.identifier.urihttp://hdl.handle.net/10722/92206-
dc.description.abstractBackground: Delayed fracture healing causes substantial disability and usually requires additional surgical treatments. Pharmacologic management to improve fracture repair would substantially improve patient outcome. The signaling pathways regulating bone healing are beginning to be unraveled, and they provide clues into pharmacologic management. The β-catenin signaling pathway, which activates T cell factor (TCF)-dependent transcription, has emerged as a key regulator in embryonic skeletogenesis, positively regulating osteoblasts. However, its role in bone repair is unknown. The goal of this study was to explore the role of β-catenin signaling in bone repair. Methods and Findings: Western blot analysis showed significant up-regulation of β-catenin during the bone healing process. Using a β-Gal activity assay to observe activation during healing of tibia fractures in a transgenic mouse model expressing a TCF reporter, we found that β-catenin-mediated, TCF-dependent transcription was activated in both bone and cartilage formation during fracture repair. Using reverse transcription-PCR, we observed that several WNT ligands were expressed during fracture repair. Treatment with DKK1 (an antagonist of WNT/β-catenin pathway) inhibited β-catenin signaling and the healing process, suggesting that WNT ligands regulate β-catenin. Healing was significantly repressed in mice conditionally expressing either null or stabilized β-catenin alleles induced by an adenovirus expressing Cre recombinase. Fracture repair was also inhibited in mice expressing osteoblast-specific β-catenin null alleles. In stark contrast, there was dramatically enhanced bone healing in mice expressing an activated form of β-catenin, whose expression was restricted to osteoblasts. Treating mice with lithium activated β-catenin in the healing fracture, but healing was enhanced only when treatment was started subsequent to the fracture. Conclusions: These results demonstrate that β-catenin functions differently at different stages of fracture repair. In early stages, precise regulation of β-catenin is required for pluripotent mesenchymal cells to differentiate to either osteoblasts or chondrocytes. Once these undifferentiated cells have become committed to the osteoblast lineage, β-catenin positively regulates osteoblasts. This is a different function for β-catenin than has previously been reported during development. Activation of β-catenin by lithium treatment has potential to improve fracture healing, but only when utilized in later phases of repair, after mesenchymal cells have become committed to the osteoblast lineage. © 2007 Chen et al.en_HK
dc.languageengen_HK
dc.publisherPublic Library of Science. The Journal's web site is located at http://medicine.plosjournals.org/perlserv/?request=index-html&issn=1549-1676en_HK
dc.relation.ispartofPLoS Medicineen_HK
dc.subjectAlleleen_HK
dc.subjectAnimal Experimenten_HK
dc.subjectAnimal Modelen_HK
dc.subjectAnimal Tissueen_HK
dc.subjectArticleen_HK
dc.subjectCartilageen_HK
dc.subjectControlled Studyen_HK
dc.subjectFracture Healingen_HK
dc.subjectFracture Nonunionen_HK
dc.subjectFracture Treatmenten_HK
dc.subjectMaleen_HK
dc.subjectMouseen_HK
dc.subjectNonhumanen_HK
dc.subjectNull Alleleen_HK
dc.subjectOssificationen_HK
dc.subjectOsteoblasten_HK
dc.subjectProtein Expressionen_HK
dc.subjectRegulatory Mechanismen_HK
dc.subjectReporter Geneen_HK
dc.subjectReverse Transcription Polymerase Chain Reactionen_HK
dc.subjectSignal Transductionen_HK
dc.subjectTibia Fractureen_HK
dc.subjectTissue Repairen_HK
dc.subjectTranscription Regulationen_HK
dc.subjectTransgenic Mouseen_HK
dc.subjectUpregulationen_HK
dc.subjectWestern Blottingen_HK
dc.titleBeta-catenin signaling plays a disparate role in different phases of fracture repair: Implications for therapy to improve bone healingen_HK
dc.typeArticleen_HK
dc.identifier.emailChen, Y:ychenc@hkucc.hku.hken_HK
dc.identifier.authorityChen, Y=rp1318en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pmed.0040249en_HK
dc.identifier.pmid17676991-
dc.identifier.pmcidPMC1950214-
dc.identifier.scopuseid_2-s2.0-34547604106en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-34547604106&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume4en_HK
dc.identifier.issue7en_HK
dc.identifier.spage1216en_HK
dc.identifier.epage1229en_HK
dc.identifier.eissn1549-1676-
dc.identifier.isiWOS:000248406300015-
dc.identifier.citeulike6834605-

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