Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response

Chan, James K, Glass, Graeme E, Ersek, Adel, Freidin, Andrew, Williams, Garry A, Gowers, Kate, Espirito Santo, Ana I, Jeffery, Rosemary, Otto, William R, Poulsom, Richard, Feldmann, Marc, Rankin, Sara M, Horwood, Nicole J ORCID: https://orcid.org/0000-0002-6344-1677 and Nanchahal, Jagdeep (2015) Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response. EMBO Molecular Medicine, 7 (5). pp. 547-561. ISSN 1757-4676

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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 24h 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.

Item Type:	Article
Additional Information:	© 2015 The Authors. Published under the terms of the CC BY 4.0 license.
Uncontrolled Keywords:	animals,drug effects,metabolism,disease models, animal,drug effects,drug therapy,humans,drug effects,mice,immunology,immunology,administration & dosage,administration & dosage,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	06 Mar 2019 11:30
Last Modified:	19 Oct 2023 02:23
URI:	https://ueaeprints.uea.ac.uk/id/eprint/70154
DOI:	10.15252/emmm.201404487

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