Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

Interleukin-1 is overexpressed in injured muscles following spinal cord injury and promotes neurogenic heterotopic ossification (#245)

Hsu-Wen HWT Tseng 1 , Irina IK Kulina 1 , Dorothée DG Girard 2 3 , Jules JG Gueguen 2 3 , Cedryck CV Vaquette 4 5 , Marjorie MS Salga 1 6 7 , Whitney WF Fleming 1 , Beulah BJ Jose 1 , Susan SM Millard 1 , Allison AP Pettit 1 , Kate KS Schroder 8 , Lawrie LW Wheeler 9 , François FG Genêt 6 7 , Sébastien SB Banzet 2 3 , Gethin GT Thomas 9 , Kylie KA Alexander 1 , Jean-Pierre JPL Levesque 1
  1. Mater Research Institute-The University of Queensland, Brisbane, Queensland, Australia
  2. Institut de Recherche Biomédicale des Armées (IRBA), Clamart, France
  3. INSERM UMRS-MD 1197, Université de Paris-Saclay, Université de Paris-Saclay, Palaiseau, France
  4. Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
  5. The University of Queensland, School of Dentistry, Herston, Brisbane, Queensland, Australia
  6. Service de Médecine Physique et de Réadaptation, Raymond Poincaré Hospital, Garches, France
  7. Versailles Saint-Quentin-en-Yvelines University (UVSQ); UFR Simone Veil - Santé, END: ICAP, INSERM U1179, University of Versailles Saint Quentin en Yvelines, Montigny le Bretonneux, France
  8. Institute for Molecular Bioscience, Institute for Molecular Bioscience,University of Queensland, Brisbane, Queensland, Australia
  9. The University of Queensland Diamantina Institute, Brisbane, Queensland, Australia

Neurogenic heterotopic ossifications (NHOs) are pathological heterotopic bones developing in periarticular muscles following central nervous system injuries including spinal cord injuries (SCI) and traumatic brain injuries (TBI). The pathobiology of NHO is poorly understood, hence the curative treatment is limited to surgical resection of pathological NHOs. Using a SCI-induced NHO mouse model with dual insults combining a spinal cord transection and a muscle injury via intramuscular injection of cardiotoxin (CDTX), we have demonstrated that macrophages-mediated inflammatory responses are required for NHO formation. In this study, we investigated the changes in muscle microenvironment that may promote NHO formation using microarray gene expression analyses on whole muscle mRNA extracts. Gene set enrichment analysis (GSEA) showed that the inflammation gene set was significantly enriched in muscles from mice with SCI and CDTX-mediated muscle injury developing NHO compared to muscle injury alone, SCI alone, or sham-SCI control groups that do not develop NHO. Genes encoding inflammatory cytokines such as interleukin-1β (IL-1β) were overexpressed in muscles developing NHO compared to muscles injured with CDTX alone. NHO development was reduced in mice with defective Il1r1 gene encoding IL-1 receptor. This suggests IL-1 signaling contributes to NHO development following SCI in mice. Interestingly, some other genes involved in inflammation, such as colony-stimulating factor-1 (CSF1), tumor necrosis factor (TNF) or C-C chemokine ligand-2 (CCL2), were also upregulated in muscles developing NHO; however, they were not critical for NHO development. Of relevance to the human pathology, IL-1β was expressed by CD68+ macrophages and osteoclasts in NHO biopsies from SCI and TBI patients. In vitro study demonstrated that IL-1α and IL-1β produced by activated human monocytes promoted calcium mineralization of fibro-adipogenic progenitors isolated from muscles surrounding NHOs. In summary, these data suggest that interleukin-1 signalling contributes to NHO development in both humans and mice.