Distinct Effects of IL-6 Classic and Trans -Signaling in Bone Fracture Healing
Open accessAbstract
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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Olamkicept selectively targets sIL-6R but not IL-6 or IL-6R, and can effectively discriminate between IL-6 classic and trans-signaling.
“olamkicept, selectively targeting sIL-6R but not IL-6 or IL-6R, can effectively discriminate between IL-6 classic and trans-signaling”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [111]
The Discussion (page unavailable) says sgp130Fc selectively binds the IL-6/sIL-6R complex and inhibits trans-signaling, supporting the distinction from classic signaling. Our copy does not name olamkicept or establish that it targets sIL-6R alone rather than the IL-6/sIL-6R complex. (LLM, conf=0.82)
Experimental — accuracy not yet measuredOlamkicept may be more beneficial than global blockade of IL-6.
“thus may be more beneficial than the global blockade of IL-6 [111, 112].”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [111]
The Discussion (page unavailable) reports that global IL-6 blockade delayed fracture healing in mice, whereas selective trans-signaling inhibition did not affect healing. This supports a possible advantage for selective blockade in that setting, but the paper studies sgp130Fc and does not name Olamkicept or establish a benefit for it beyond the mouse fracture model. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAnimal models have demonstrated the primary role of IL-6 trans-signaling in inflammatory diseases.
“as evidences from animal models have demonstrated the primary role of IL-6 trans-signaling in inflammatory diseases”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [111]
The introductory passage describes IL-6 trans-signaling as a proposed driver of proinflammatory reactions, which supports the general connection to inflammation. But the paper does not establish a primary role across inflammatory diseases: in its uncomplicated fracture mouse model, the IL-6 Signaling in Bone Fracture Healing section reports only minor effects from selectively blocking trans-signaling and a crucial role for classic signaling in local immune-cell recruitment (page unavailable). (LLM, conf=0.84)
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- Authors
- Prystaz, K., Kaiser, K., Kovtun, A., Haffner-Luntzer, M., Fischer, V., Rapp, A. E., Liedert, A., Strauss, G., Waetzig, G. H., Rose-John, S., & Ignatius, A.
- Affiliations
- Universität Ulm (DE)
- Conaris (DE)
- Corresponding author
- Ignatius, Anita
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 188
- Issue
- 2
- Pages
- 474-490
- ISSN
- 0002-9440 (ISSN-L)
- OpenAlex
- W2771055284
- Cited by
- 142
- References
- 8
- Citations by year
- 2026: 18 · 2025: 18 · 2024: 22 · 2023: 13 · 2022: 14 · 2021: 13 · 2020: 23 · 2019: 7 · 2018: 14
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- OPen Access Repositorium der Universität Ulm (OPARU) (Ulm University) (submittedVersion, cc-by-nc-nd)
- Universität Ulm, Kommunikations- und Informationszentrum (kiz)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Epidemiology › Bone fractures and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- interleukin-6, IL-6 trans-signaling, fracture healing, osteotomy, gp130, anti-IL-6 antibody, systemic inflammation, immune cell recruitment, bone regeneration, bone remodeling, bone formation
- MeSH terms
- Animals, Bony Callus, Femur, Inflammation, Male, Mice, Inbred C57BL, Osteogenesis, Osteotomy, Signal Transduction, Interleukin-6, Cytokines, Bone Remodeling, Fracture Healing, Inflammation Mediators, Chemokines, Receptors, Interleukin-6, X-Ray Microtomography
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