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Pharmacological inhibition of IL-6 trans-signaling improves compromised fracture healing after severe trauma.

ABSTRACT: Patients with multiple injuries frequently suffer bone fractures and are at high risk to develop fracture healing complications. Because of its key role both in systemic posttraumatic inflammation and fracture healing, the pleiotropic cytokine interleukin-6 (IL-6) may be involved in the pathomechanisms of trauma-induced compromised fracture healing. IL-6 signals are transmitted by two different mechanisms: classic signaling via the membrane-bound receptor (mIL-6R) and trans-signaling via its soluble form (sIL-6R). Herein, we investigated whether IL-6 classic and trans-signaling play different roles in bone regeneration after severe injury. Twelve-week-old C57BL/6J mice underwent combined femur osteotomy and thoracic trauma. To study the function of IL-6, either an anti-IL-6 antibody, which inhibits both IL-6 classic and trans-signaling, or a soluble glycoprotein 130 fusion protein (sgp130Fc), which selectively blocks trans-signaling, were injected 30 min and 48 h after surgery. Bone healing was assessed using cytokine analyses, flow cytometry, histology, micro-computed tomography, and biomechanical testing. Selective inhibition of IL-6 trans-signaling significantly improved the fracture healing outcome after combined injury, as confirmed by accelerated cartilage-to-bone transformation, enhanced bony bridging of the fracture gap and improved mechanical callus properties. In contrast, global IL-6 inhibition did not affect compromised fracture healing. These data suggest that classic signaling may mediate beneficial effects on bone repair after severe injury. Selective inhibition of IL-6 trans-signaling might have therapeutic potential to treat fracture healing complications in patients with concomitant injuries.

SUBMITTER: Kaiser K

PROVIDER: S-EPMC5889421 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Pharmacological inhibition of IL-6 trans-signaling improves compromised fracture healing after severe trauma.

Kaiser Kathrin K Prystaz Katja K Vikman Anna A Haffner-Luntzer Melanie M Bergdolt Stephanie S Strauss Gudrun G Waetzig Georg H GH Rose-John Stefan S Ignatius Anita A

Naunyn-Schmiedeberg's archives of pharmacology 20180301 5

Patients with multiple injuries frequently suffer bone fractures and are at high risk to develop fracture healing complications. Because of its key role both in systemic posttraumatic inflammation and fracture healing, the pleiotropic cytokine interleukin-6 (IL-6) may be involved in the pathomechanisms of trauma-induced compromised fracture healing. IL-6 signals are transmitted by two different mechanisms: classic signaling via the membrane-bound receptor (mIL-6R) and trans-signaling via its sol ...[more]

PMID: 29497762

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Project description:IntroductionAn aging population in developed countries has increased the number of osteoporotic hip fractures and will continue to grow over the next decades. Previous studies have investigated the effect of integrated orthogeriatric trauma units and care model on outcomes of hip fracture patients. Although all of the models perform better than usual care, there is no conclusive evidence which care model is superior. More confirmative studies reporting the efficacy of orthogeriatric trauma units are needed. The objective of this study was to evaluate outcomes of hip fracture patients admitted to the hospital before and after implementation of an orthogeriatric trauma unit.Materials and methodsThis retrospective cohort study was conducted at a level 2 trauma center between 2016 and 2018. Patients aged 70 years or older with a hip fracture undergoing surgery were included to evaluate the implementation of an orthogeriatric trauma unit. The main outcomes were postoperative complications, patient mortality, time spent at the emergency department, time to surgery, and hospital length of stay.ResultsA total of 806 patients were included. After implementation of the orthogeriatric trauma unit, there was a significant decrease in postoperative complications (42% vs. 49% in the historical cohort, p = 0.034), and turnaround time at the emergency department was reduced by 38 minutes. Additionally, there was significantly less missing data after implementation of the orthogeriatric trauma unit. After correcting for covariates, patients in the orthogeriatric trauma unit cohort had a lower chance of complications (OR 0.654, 95% CI 0.471-0.908, p = 0.011) and a lower chance of 1-year mortality (OR 0.656, 95% CI 0.450-0.957, p = 0.029).ConclusionsThis study showed that implementation of an orthogeriatric trauma unit leads to a decrease in postoperative complications, 1-year mortality, and time spent at the emergency department, while also improving the quality of data registration for clinical studies.Level of evidenceLevel III.

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Pharmacological inhibition of IL-6 trans-signaling improves compromised fracture healing after severe trauma.

Publications

Pharmacological inhibition of IL-6 trans-signaling improves compromised fracture healing after severe trauma.

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