title: Enhanced Calvarial Bone Healing in CD11c-TLR4-/- and MyD88-/- Mice.
abstract: BACKGROUND
  Inflammation is integral to the injury response. The inflammatory response is essential to the host defense against infection and also to tissue regeneration and repair. Toll-like receptors (TLRs) are critical activators of the innate immune response and present attractive therapeutic targets for inflammation-modulated tissue regeneration. The authors' previous study showed that depletion of TLR4 resulted in accelerated skull bone healing concurrent with increased expression of osteoclastogenic genes. As such, in the present study, the authors used various knockout mouse models for TLR4 and its associated signaling mediators as tools to further understand the role of Toll-like receptor-mediated inflammation in calvarial bone healing.
  
  
  METHODS
  Calvarial defects (1.8-mm diameter) were created in wild-type, TLR4 knockout (TLR4), TLR2, MyD88, TRIF, TLR4 knockout in myeloid cell (Lyz-TLR4), and TLR4 knockout in dendritic-lineage cell (CD11c-TLR4) mice. Bone healing was examined using micro-computed tomographic, histologic, and histomorphometric analyses.
  
  
  RESULTS
  Micro-computed tomographic and histomorphometric analyses revealed that TLR4-deficient mice (TLR4, Lyz-TLR4, and CD11c-TLR4) exhibited a faster intramembraneous healing response at postoperative day 7, whereas MyD88 and CD11c-TLR4 mice showed enhanced bone healing at day 28.
  
  
  CONCLUSIONS
  The authors' data suggest a detrimental role for TLR4 in CD11c cells, mediated by Myd88 signaling, during calvarial bone healing. The authors have demonstrated that Toll-like receptor signaling components affect calvarial bone healing, establishing a link between the skeletal and immune systems during craniofacial bone healing. Toll-like receptor signaling components might be used to initiate enhanced healing in bone defects to improve clinical outcomes.
authors.affiliation: Shanghai, People's Republic of China; Pittsburgh, Pa.; and Baltimore, Md.|From the Department of Stomatology, Tenth People's Hospital of Tongji University; the Departments of Plastic Surgery, Surgery, Oral Biology, and Bioengineering, University of Pittsburgh; and the Department of Surgery, The Johns Hopkins University.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Shanghai, People's Republic of China; Pittsburgh, Pa.; and Baltimore, Md.|From the Department of Stomatology, Tenth People's Hospital of Tongji University; the Departments of Plastic Surgery, Surgery, Oral Biology, and Bioengineering, University of Pittsburgh; and the Department of Surgery, The Johns Hopkins University.
authors.forename: Gwen M
authors.initials: GM
authors.lastname: Taylor
authors.affiliation: Shanghai, People's Republic of China; Pittsburgh, Pa.; and Baltimore, Md.|From the Department of Stomatology, Tenth People's Hospital of Tongji University; the Departments of Plastic Surgery, Surgery, Oral Biology, and Bioengineering, University of Pittsburgh; and the Department of Surgery, The Johns Hopkins University.
authors.forename: James R
authors.initials: JR
authors.lastname: Gilbert
authors.affiliation: Shanghai, People's Republic of China; Pittsburgh, Pa.; and Baltimore, Md.|From the Department of Stomatology, Tenth People's Hospital of Tongji University; the Departments of Plastic Surgery, Surgery, Oral Biology, and Bioengineering, University of Pittsburgh; and the Department of Surgery, The Johns Hopkins University.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Losee
authors.affiliation: Shanghai, People's Republic of China; Pittsburgh, Pa.; and Baltimore, Md.|From the Department of Stomatology, Tenth People's Hospital of Tongji University; the Departments of Plastic Surgery, Surgery, Oral Biology, and Bioengineering, University of Pittsburgh; and the Department of Surgery, The Johns Hopkins University.
authors.forename: Chhinder P
authors.initials: CP
authors.lastname: Sodhi
authors.affiliation: Shanghai, People's Republic of China; Pittsburgh, Pa.; and Baltimore, Md.|From the Department of Stomatology, Tenth People's Hospital of Tongji University; the Departments of Plastic Surgery, Surgery, Oral Biology, and Bioengineering, University of Pittsburgh; and the Department of Surgery, The Johns Hopkins University.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hackam
authors.affiliation: Shanghai, People's Republic of China; Pittsburgh, Pa.; and Baltimore, Md.|From the Department of Stomatology, Tenth People's Hospital of Tongji University; the Departments of Plastic Surgery, Surgery, Oral Biology, and Bioengineering, University of Pittsburgh; and the Department of Surgery, The Johns Hopkins University.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Shanghai, People's Republic of China; Pittsburgh, Pa.; and Baltimore, Md.|From the Department of Stomatology, Tenth People's Hospital of Tongji University; the Departments of Plastic Surgery, Surgery, Oral Biology, and Bioengineering, University of Pittsburgh; and the Department of Surgery, The Johns Hopkins University.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cooper
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000235:genetics / Q000502:physiology*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D012886:Skull / Q000293:injuries*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D039521:CD11c Antigen; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4