INSIGHT INTO THE INTERDEPENDENCY OF OBESITY/DIABETES, BONE HEALING CAPACITY, AND IMMUNE RESPONSE

Bone homeostasis as well as bone regeneration are known to be impaired in elderly patients. Rising evidence suggests that the fracture healing outcome is affected by an accumulation of experienced or ‘aged’ effector/memory T cells, causing ‘inflamm-aging’ and disturbing the balance between bone resorption and regeneration. It is also well-established that age-associated type 2 diabetes mellitus (T2DM) caused by obesity has been revealed as one of the risk factors for healing complications leading to malunions and nonunions. The aspect of impaired fracture healing preferentially occurring in obese and aged individuals is even more interesting, as the increased inflammatory response seen in both conditions could be the mutual cause. We analyzed the cellular changes of the immune system through flow cytometry in an obese animal bone healing model in respect to glucose tolerance and the effects on the healing outcome. Healing outcome was determined by computer tomography and histology. Expression analysis and cytokine profiles revealed changes in the extracellular matrix composition and immune response. Obese mice were divided into two groups according to their glucose tolerance. The group with high glucose tolerance corresponded more to a prediabetic phenotype, while the group with low glucose tolerance could be assigned to the diabetic phenotype. Delayed bone healing was observed in the prediabetic group in particular. These healing delays could be associated with proinflammatory reactions to the bone injury. The observed changes in the composition of the extracellular matrix could be corrected by immunomodulation that reduced the effector/memory T cells. This study showed an interdependency between the metabolic status, the immunological reaction and the regenerative bone healing capacity and a possibility to alter the healing outcome by an immunomodulatory approach.