The inflammatory cytokine Oncostatin M is a mediator of neurological heterotopic ossification — ASN Events
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  3. The inflammatory cytokine Oncostatin M is a mediator of neurological heterotopic ossification

The inflammatory cytokine Oncostatin M is a mediator of neurological heterotopic ossification (#391)

Kylie A Alexander 1 , Hsu-Wen Tseng 1 , Frederic Torossian 2 , Irina Kulina 1 , Bernadette Guerton 2 , Beulah Jose 1 , Marjorie Salga 1 3 , François Genet 3 4 , Natalie A Sims 5 , Jean-Jacques Lataillade 2 6 , Marie-Caroline Le Bousse-Kerdiles 2
  1. Mater Research, The University of Queensland, Brisbane, Queensland, Australia
  2. INSERM UMR-MD-1197, SToRM, Clamart, France
  3. END:ICAP U1179 INSERM, UFR Simone Veil-Santé, University of Versailles Saint Quentin en Yvelines, Montigny le Bretonneux, France
  4. Université Paris 12, Service de Médecine Physique et de Réadaptation, Garches, France
  5. Saint Vincent Institute, Fitzroy, VIC, Australia
  6. CTSA, IRBA, Rue Raoul Batany,, Clamart, France

Neurological heterotopic ossification (NHO) is a frequent complication of spinal cord and traumatic brain injuries, which manifests as abnormal ossification of soft tissues. NHO is debilitating, causing pain, joint ankylosis and vascular and nerve compression. The mechanisms leading to NHO are unknown and the only effective treatment is surgical resection. To elucidate NHO pathophysiology we developed the first murine model of NHO1. Mice underwent spinal cord injury (SCI), and muscular injury was induced by a cardiotoxin (CDTX) injection in the hind limbs. SCI or CDTX alone didn’t induce NHO, however the combination of SCI+CDTX induced NHO in the injected limb, which is consistent with clinical observations. Using this model, we have shown that macrophages are key mediators of NHO as clodronate-loaded liposome treatment in SCI+CDTX mice prevents NHO. Microarrays were performed using RNA isolated from muscles of mice after SCI+CDTX, and data confirmed a significant upregulation of the cytokine Oncostatin M (OSM). Osm mRNA was significantly increased in muscles of SCI+CDTX mice compared to SHAM+CDTX. MicroCT confirmed significantly reduced NHO in Osmr-/- mice compared to wild-type, and immunohistochemistry confirmed OSM expression in damaged muscles after SCI. Recombinant mouse OSM significantly enhanced the osteogenic potential of muscle progenitor cells (satellite cells and interstitial cells) sorted from naïve mice using in vitro osteogenic assays. In human NHO patients, OSM plasma concentrations were significantly elevated compared to healthy donors. OSM was produced by CD14+ NHO-associated mononuclear cells (HO-mac) after LPS stimulation. Recombinant human OSM enhanced the mineralization and expression of osteoblast specific proteins in muscle-derived stromal cells surrounding NHO (HO-MDSC). Finally, conditioned media from LPS-stimulated HO-macs significantly enhanced HO-MDSC osteogenic potential, which was reversed by neutralizing anti-OSM antibodies. Altogether, our results in mice and patients suggest that macrophages contribute to neurogenic HO formation through the osteogenic action of OSM on muscle cells.

  1. References 1. Genet F, Kulina I, Vaquette C, Torossian F, Millard S, Pettit AR et al. Neurological heterotopic ossification following spinal cord injury is triggered by macrophage-mediated inflammation in muscle. The Journal of pathology 2015; 236(2): 229-40.
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