Distinct effects of interleukin-6 classic and trans-signaling in bone fracture healing.

Katja Prystaz, Kathrin Kaiser, Anna Kovtun, Melanie Haffner-Luntzer, Verena Fischer, Anna E Rapp, Astrid Liedert, Gudrun Strauss, Georg H Waetzig, Stefan Rose-John, Anita Ignatius
Year of publication:
Journal title abbreviated:
Am. J. Pathol.
Journal title long:
The American journal of pathology
Impact factor:
Bone healing is a complex process with closely linked phases of inflammation, regeneration, and remodeling. Interleukin-6 (IL-6) may crucially regulate this process; however, the underlying mechanisms are presently unclear. IL-6 signals are transmitted via the transmembrane glycoprotein 130 by two distinct mechanisms: classic signaling employing the membrane-anchored IL-6 receptor, and trans-signaling using its soluble form. Here, 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 received 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 sgp130Fc, 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 post-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.