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Accelerated Calvarial Healing in Mice Lacking Toll-Like Receptor 4

Wang, D and Gilbert, JR and Cray, JJ and Kubala, AA and Shaw, MA and Billiar, TR and Cooper, GM (2012) Accelerated Calvarial Healing in Mice Lacking Toll-Like Receptor 4. PLoS ONE, 7 (10).

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The bone and immune systems are closely interconnected. The immediate inflammatory response after fracture is known to trigger a healing cascade which plays an important role in bone repair. Toll-like receptor 4 (TLR4) is a member of a highly conserved receptor family and is a critical activator of the innate immune response after tissue injury. TLR4 signaling has been shown to regulate the systemic inflammatory response induced by exposed bone components during long-bone fracture. Here we tested the hypothesis that TLR4 activation affects the healing of calvarial defects. A 1.8 mm diameter calvarial defect was created in wild-type (WT) and TLR4 knockout (TLR4 ) mice. Bone healing was tested using radiographic, histologic and gene expression analyses. Radiographic and histomorphometric analyses revealed that calvarial healing was accelerated in TLR4 mice. More bone was observed in TLR4 mice compared to WT mice at postoperative days 7 and 14, although comparable healing was achieved in both groups by day 21. Bone remodeling was detected in both groups on postoperative day 28. In TLR4 mice compared to WT mice, gene expression analysis revealed that higher expression levels of IL-1β, IL-6, TNF-α,TGF-β1, TGF-β3, PDGF and RANKL and lower expression level of RANK were detected at earlier time points (≤ postoperative 4 days); while higher expression levels of IL-1β and lower expression levels of VEGF, RANK, RANKL and OPG were detected at late time points (> postoperative 4 days). This study provides evidence of accelerated bone healing in TLR4 mice with earlier and higher expression of inflammatory cytokines and with increased osteoclastic activity. Further work is required to determine if this is due to inflammation driven by TLR4 activation. © 2012 Wang et al. -/- -/- -/- -/- -/-


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Wang, Ddaw112@pitt.eduDAW112
Gilbert, JRjrg101@pitt.eduJRG101
Cray, JJ
Kubala, AA
Shaw, MA
Billiar, TRbilliar@pitt.eduBILLIAR
Cooper, GMgmc8@pitt.eduGMC8
ContributionContributors NameEmailPitt UsernameORCID
Date: 10 October 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0046945
Schools and Programs: School of Medicine > Surgery
Swanson School of Engineering > Bioengineering
Refereed: Yes
PubMed ID: 23071670
Date Deposited: 18 Oct 2012 20:48
Last Modified: 30 Mar 2021 13:56


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