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Am J Pathol. 2018 Feb;188(2):474-490. doi: 10.1016/j.ajpath.2017.10.011. Epub 2017 Nov 13.

Distinct Effects of IL-6 Classic and Trans-Signaling in Bone Fracture Healing.

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Institute of Orthopedic Research and Biomechanics, Trauma Research Center Ulm, Germany.
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
CONARIS Research Institute AG, Kiel, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Institute of Orthopedic Research and Biomechanics, Trauma Research Center Ulm, Germany. Electronic address:


Bone healing is a complex process with closely linked phases of inflammation, regeneration, and remodeling. IL-6 may crucially regulate this process; however, the underlying mechanisms are unclear. IL-6 signals are transmitted via the transmembrane glycoprotein 130 by two distinct mechanisms: classic signaling using the membrane-anchored IL-6 receptor and trans-signaling using its soluble form. Herein, we investigated the hypothesis that IL-6 classic and trans-signaling have different functions during bone healing. To investigate fracture healing, 12-week-old C57BL/6J mice underwent a femur osteotomy. To study the function of IL-6 during the inflammatory phase, either an anti-IL-6 antibody, which inhibits IL-6 classic and trans-signaling, or soluble glycoprotein 130 fusion protein, which selectively blocks trans-signaling, was injected after 30 minutes and 48 hours. To analyze IL-6 effects in the repair phase, compounds were injected from day 7 onwards. Global IL-6 inhibition in the early phase after fracture reduced systemic inflammation, the recruitment of immune cells, and bone regeneration, resulting in delayed fracture healing. Global IL-6 inhibition during the repair phase disturbed bone formation and remodeling. In contrast, inhibition of IL-6 trans-signaling exerted minor effects on the immune response and did not influence bone repair, suggesting that the classic pathway accounts for most of the effects observed after global IL-6 inhibition. Our results reveal that IL-6 classic signaling, but not IL-6 trans-signaling, is essential for bone repair.

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