title: Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response.
abstract: The mechanism by which trauma initiates healing remains unclear. Precise understanding of these events may define interventions for accelerating healing that could be translated to the clinical arena. We previously reported that addition of low-dose recombinant human TNF (rhTNF) at the fracture site augmented fracture repair in a murine tibial fracture model. Here, we show that local rhTNF treatment is only effective when administered within 24 h of injury, when neutrophils are the major inflammatory cell infiltrate. Systemic administration of anti-TNF impaired fracture healing. Addition of rhTNF enhanced neutrophil recruitment and promoted recruitment of monocytes through CCL2 production. Conversely, depletion of neutrophils or inhibition of the chemokine receptor CCR2 resulted in significantly impaired fracture healing. Fragility, or osteoporotic, fractures represent a major medical problem as they are associated with permanent disability and premature death. Using a murine model of fragility fractures, we found that local rhTNF treatment improved fracture healing during the early phase of repair. If translated clinically, this promotion of fracture healing would reduce the morbidity and mortality associated with delayed patient mobilization.
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: James K
authors.initials: JK
authors.lastname: Chan
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Graeme E
authors.initials: GE
authors.lastname: Glass
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Adel
authors.initials: A
authors.lastname: Ersek
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Freidin
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Garry A
authors.initials: GA
authors.lastname: Williams
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Gowers
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Espirito Santo
authors.affiliation: Histopathology Laboratory and In Situ Hybridisation Service, Cancer Research UK - London Research Institute, London, UK.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Jeffery
authors.affiliation: Histopathology Laboratory and In Situ Hybridisation Service, Cancer Research UK - London Research Institute, London, UK.
authors.forename: William R
authors.initials: WR
authors.lastname: Otto
authors.affiliation: Histopathology Laboratory and In Situ Hybridisation Service, Cancer Research UK - London Research Institute, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Rankin
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Horwood
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK jagdeep.nanchahal@kennedy.ox.ac.uk.
authors.forename: Jagdeep
authors.initials: J
authors.lastname: Nanchahal
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D017102:Fracture Healing / Q000187:drug effects* / Q000276:immunology; D050723:Fractures, Bone / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D051379:Mice; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha
keywords: CCL2; TNF; bone; fracture; inflammation