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- Publisher Website: 10.1371/journal.pmed.0040249
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- PMID: 17676991
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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
Title | Beta-catenin signaling plays a disparate role in different phases of fracture repair: Implications for therapy to improve bone healing |
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Authors | |
Keywords | Allele 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 Date | 2007 |
Publisher | Public 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? |
Abstract | Background: 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 Identifier | http://hdl.handle.net/10722/92206 |
ISSN | 2023 Impact Factor: 10.5 2023 SCImago Journal Rankings: 4.198 |
PubMed Central ID | |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Chen, Y | en_HK |
dc.contributor.author | Whetstone, HC | en_HK |
dc.contributor.author | Lin, AC | en_HK |
dc.contributor.author | Nadesan, P | en_HK |
dc.contributor.author | Wei, Q | en_HK |
dc.contributor.author | Poon, R | en_HK |
dc.contributor.author | Alman, BA | en_HK |
dc.date.accessioned | 2010-09-17T10:39:12Z | - |
dc.date.available | 2010-09-17T10:39:12Z | - |
dc.date.issued | 2007 | en_HK |
dc.identifier.citation | PLoS Medicine, 2007, v. 4 n. 7, p. 1216-1229 | en_HK |
dc.identifier.issn | 1549-1277 | en_HK |
dc.identifier.uri | http://hdl.handle.net/10722/92206 | - |
dc.description.abstract | Background: 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.language | eng | en_HK |
dc.publisher | Public Library of Science. The Journal's web site is located at http://medicine.plosjournals.org/perlserv/?request=index-html&issn=1549-1676 | en_HK |
dc.relation.ispartof | PLoS Medicine | en_HK |
dc.subject | Allele | en_HK |
dc.subject | Animal Experiment | en_HK |
dc.subject | Animal Model | en_HK |
dc.subject | Animal Tissue | en_HK |
dc.subject | Article | en_HK |
dc.subject | Cartilage | en_HK |
dc.subject | Controlled Study | en_HK |
dc.subject | Fracture Healing | en_HK |
dc.subject | Fracture Nonunion | en_HK |
dc.subject | Fracture Treatment | en_HK |
dc.subject | Male | en_HK |
dc.subject | Mouse | en_HK |
dc.subject | Nonhuman | en_HK |
dc.subject | Null Allele | en_HK |
dc.subject | Ossification | en_HK |
dc.subject | Osteoblast | en_HK |
dc.subject | Protein Expression | en_HK |
dc.subject | Regulatory Mechanism | en_HK |
dc.subject | Reporter Gene | en_HK |
dc.subject | Reverse Transcription Polymerase Chain Reaction | en_HK |
dc.subject | Signal Transduction | en_HK |
dc.subject | Tibia Fracture | en_HK |
dc.subject | Tissue Repair | en_HK |
dc.subject | Transcription Regulation | en_HK |
dc.subject | Transgenic Mouse | en_HK |
dc.subject | Upregulation | en_HK |
dc.subject | Western Blotting | en_HK |
dc.title | Beta-catenin signaling plays a disparate role in different phases of fracture repair: Implications for therapy to improve bone healing | en_HK |
dc.type | Article | en_HK |
dc.identifier.email | Chen, Y:ychenc@hkucc.hku.hk | en_HK |
dc.identifier.authority | Chen, Y=rp1318 | en_HK |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.1371/journal.pmed.0040249 | en_HK |
dc.identifier.pmid | 17676991 | - |
dc.identifier.pmcid | PMC1950214 | - |
dc.identifier.scopus | eid_2-s2.0-34547604106 | en_HK |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-34547604106&selection=ref&src=s&origin=recordpage | en_HK |
dc.identifier.volume | 4 | en_HK |
dc.identifier.issue | 7 | en_HK |
dc.identifier.spage | 1216 | en_HK |
dc.identifier.epage | 1229 | en_HK |
dc.identifier.eissn | 1549-1676 | - |
dc.identifier.isi | WOS:000248406300015 | - |
dc.identifier.citeulike | 6834605 | - |
dc.identifier.issnl | 1549-1277 | - |