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Bone Abstracts (2014) 3 OC1.5 | DOI: 10.1530/boneabs.3.OC1.5

Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.

Fractures are very common and affect 2% of the population per annum. Fragility fractures represent the greatest unmet need and are associated with high rates of morbidity and mortality. Currently, there is no approved therapy for enhancing healing of fragility fractures. We previously reported that upregulation of the early inflammatory response following skeletal injury can promote fracture repair (Glass et al PNAS 2011). Inflammation represents the earliest response following trauma and initiates a cascade of downstream events crucial for wound healing. However, the mechanism by which this occurs remains poorly defined. The earliest event following injury is the release of endogenous danger signals, or alarmins, by injured or necrotic cells. These initiate the innate inflammatory response by stimulating proinflammatory cytokine production and recruitment of leukocytes. HMGB1 and S100A8 are the best characterized alarmins. We set out to establish the role of HMGB1 and S100A8/A9 in fracture repair. By generating fracture supernatants using human patient samples, we found that HMGB1 and S100A8/A9 are released locally during skeletal injury and that their levels correlated with their osteogenic activity on primary human mesenchymal stromal cells. In our murine fracture model, we found that HMGB1 and S100A8/9 are released locally and systemically immediately following injury. Furthermore, murine fracture supernatants stimulated alternatively activated macrophages and dendritic cells to express KC and IL-6, key neutrophil chemoattractants. Finally, local addition of rHMGB1 at the fracture site enhanced fracture healing by day 28 in our murine fracture model. A detailed understanding of how the upstream events initiate fracture repair is a necessary step in the development of therapeutics to enhance this process. Interventions targeting these events would allow effective clinical translation as the therapeutic would be administered at the time of fracture reduction and surgical fixation.

Volume 3

European Calcified Tissue Society Congress 2014

Prague, Czech Republic
17 May 2014 - 20 May 2014

European Calcified Tissue Society 

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