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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Remodeling / immunology
  • Bony Callus / immunology
  • Chemokines / blood
  • Cytokines / blood
  • Femur / physiology
  • Femur / surgery
  • Fracture Healing / immunology*
  • Inflammation / immunology
  • Inflammation Mediators / immunology
  • Interleukin-6 / immunology*
  • Male
  • Mice, Inbred C57BL
  • Osteogenesis / immunology
  • Osteotomy
  • Receptors, Interleukin-6 / immunology
  • Signal Transduction / immunology
  • X-Ray Microtomography


  • Chemokines
  • Cytokines
  • Inflammation Mediators
  • Interleukin-6
  • Receptors, Interleukin-6
  • interleukin-6, mouse