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

Kathrin Kaiser,Melanie Haffner-Luntzer,Gudrun Strauss,Georg H Waetzig,Katja Prystaz,Anna Vikman,Stephanie Bergdolt,Stefan Rose-John,Anita Ignatius

doi:10.1007/s00210-018-1483-7

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.

Highlights

IntroductionIL-6 is considered to be a key mediator in this complex scenario because of its significant correlation with injury severity and clinical complications (Alper et al 2016; Cuschieri et al 2010; Frink et al 2009; Gebhard et al 2000)
Patients with multiple injuries frequently suffer from bone fractures and are at high risk to develop fracture healingElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.24118 Kiel, Germany complications, including non-unions (Bhandari et al 2003; Karladani et al 2001; Zura et al 2016)
Global IL-6 inhibition does not influence compromised bone repair induced by combined fracture and thoracic trauma

Summary

Introduction

IL-6 is considered to be a key mediator in this complex scenario because of its significant correlation with injury severity and clinical complications (Alper et al 2016; Cuschieri et al 2010; Frink et al 2009; Gebhard et al 2000). It provokes both pro-inflammatory and protective effects. IL-6 contributes to the resolution of inflammation, for example, by inducing the shift from pro-inflammatory M1 to anti-inflammatory M2 macrophages (Mauer et al 2014) and the recruitment of mesenchymal stem cells from their niches (Loi et al 2016)

Methods

Results

Conclusion