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Endodontic Infection–induced Inflammation Resembling Osteomyelitis of the Jaws in Toll-like Receptor 2/Interleukin 10 Double-knockout Mice

      Highlights

      • To date, no animal models of endodontic infection–induced osteomyelitis of the jaws have been reported, limiting our knowledge of the host factors that affect the onset and course of osteomyelitis.
      • The pathogenesis of endodontic infection-induced inflammation resembling osteomyelitis of the jaws was characterized in toll-like receptor 2/interleukin 10 double deficient (TLR2/IL-10-dKO) mice.
      • TLR2/IL-10 dKO mice exhibited rapid progression of osteolytic acute inflammation within 10 days postinfection.
      • TLR2/IL-10 dKO mice surprisingly underwent spontaneous resolution of inflammation with reparative bone formation by day 21.
      • Hypoxia-inducible factor 1 alpha subunit and arginase-1 appear to be crucial factors in spontaneous wound healing in the course of osteomyelitis-like inflammation in this model.'

      Abstract

      Introduction

      In general, mice develop chronic and nonhealing periapical lesions after endodontic infection. Surprisingly, we recently found that toll-like receptor 2 (TLR2)/interleukin 10 (IL-10) double-knockout (dKO) mice exhibited acute but resolving osteomyelitislike inflammation. In this study, we examined the kinetics of endodontic infection–induced inflammation in TLR2/IL-10 dKO mice and explored a potential mechanism of periapical wound healing mediated by the hypoxia-inducible factor 1 alpha (HIF-1α) subunit and arginase 1.

      Methods

      TLR2/IL-10 dKO and wild-type C57BL/6J mice were subjected to endodontic infection in the mandibular first molars. Mice were sacrificed on days 0 (noninfected), 10, and 21 postinfection. The extent of bone destruction, inflammation, bone deposition, and gene expression were determined by micro–computed tomographic imaging, histology, bone polychrome labeling, and microarray analysis. In addition, the effect of blocking endogenous HIF-1α was tested in infected TLR2/IL-10 dKO mice using the specific inhibitor YC-1.

      Results

      Infected TLR2/IL-10 dKO mice exhibited extensive bone destruction and inflammation on day 10 followed by spontaneous periapical wound healing including bone formation and resolution of inflammation by day 21 postinfection. In contrast, WT mice developed increasing chronic periapical inflammation over the 21-day observation period. Gene expression analyses and immunohistochemistry revealed that HIF-1α and arginase 1 were up-regulated in spontaneous wound healing in TLR2/IL-10 dKO mice. Blocking of HIF-1α in TLR2/IL-10 dKO mice using YC-1 resulted in significant inhibition of regenerative bone formation.

      Conclusions

      The TLR2/IL-10 dKO mouse is a novel model resembling osteomyelitis of the jaws in which HIF-1α and arginase 1 appear to be crucial factors in spontaneous wound healing and bone repair.

      Key Words

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