Interleukin-6 Does Not Contribute to Neurogenic Heterotopic Ossification Pathogenesis
Neurogenic heterotopic ossifications (NHOs) are ectopic bones developing in periarticular muscles after severe central nervous system injuries such as spinal cord injuries (SCI) and traumatic brain injuries (TBI). The pathogenesis of NHO is still poorly understood, and the only effective therapy rem...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Mary Ann Liebert
2024-11-01
|
| Series: | Neurotrauma Reports |
| Subjects: | |
| Online Access: | https://www.liebertpub.com/doi/10.1089/neur.2024.0106 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Neurogenic heterotopic ossifications (NHOs) are ectopic bones developing in periarticular muscles after severe central nervous system injuries such as spinal cord injuries (SCI) and traumatic brain injuries (TBI). The pathogenesis of NHO is still poorly understood, and the only effective therapy remains surgical resection. Using our unique mouse model of NHO development after SCI and muscle injury, we have previously shown that oncostatin M (OSM), a cytokine of the interleukin-6 (IL-6) superfamily, contributes to NHO pathogenesis. However, a possible role of IL-6 in NHO pathogenesis remains unexplored. Herein, we establish that IL-6 mRNA is significantly upregulated in muscles developing NHO after SCI and that IL-6 protein is significantly elevated in the blood of mice developing NHO. However, administration of anti-IL-6 and anti-IL-6 receptor α chain (IL6RA) neutralizing antibodies after SCI and muscle injury did not impact NHO development. Relevant to the human pathology, recombinant human IL-6 and/or soluble IL-6 receptor α chain (sIL6RA) did not increase the mineralization of human fibro-adipogenic progenitors (FAPs) isolated from muscles surrounding NHO biopsies or the expression of osteoblast genes. As we have previously shown that macrophages are critical for NHO development, we also examined an indirect role of IL-6 on FAPs via peripheral blood monocytes. Results showed that conditioned media from human CD14+ monocytes stimulated with either IL-6 and/or sIL6RA did not increase NHO mineralization or expression of osteoblast genes. Finally, we show that mRNA for IL6RA were expressed at low levels in mesenchymal progenitors isolated from mouse and human muscles compared with OSM receptor α chain and GP130 mRNA which were abundantly expressed by these cells. Overall, our findings suggest that the contribution of the IL-6 pathway to NHO pathogenesis is minimal and that treatment with IL6RA or IL-6 neutralizing antibodies is unlikely to have beneficial effect to stop the development of this pathology. |
|---|---|
| ISSN: | 2689-288X |