Oncostatin M: a mediator of neurological heterotopic ossification — ASN Events
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Oncostatin M: a mediator of neurological heterotopic ossification (#36)

Kylie A Alexander 1 , Frederic Torossian 2 , Hsu-Wen Tseng 1 , Irina Kulina 1 , Bernadette Guerton 2 , Beulah Jose 1 , Marjorie Salga 1 3 , François Genet 3 4 , Allison Pettit 1 , Natalie A Sims 5 , Jean-Jacques Lataillade 2 , Marie-Caroline Le Bousse-kerdiles 2 , Jean-Pierre Levesque 1 6
  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 near joints. NHO is debilitating, causing pain, 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), followed by muscular injury induced by a cardiotoxin (CDTX) injection in the hind limbs. SCI or CDTX alone did not induce NHO, however the combination of SCI + intramuscular CDTX induced NHO in the injected limb, which is consistent with clinical observations. Microarrays were performed using RNA isolated from muscles of mice after SCI, and data confirmed a significant upregulation of the cytokine Oncostatin M (OSM) gene. Osm mRNA was significantly increased in muscles of mice that underwent SCI + CDTX compared to SHAM + CDTX. MicroCT confirmed significantly reduced NHO in Osmr-/- mice compared to control mice, and immunohistochemistry confirmed the expression of OSM 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 by in vitro osteogenic assays. In human NHO patients, OSM plasma concentrations were significantly elevated compared to healthy donors. Similar to mouse studies, recombinant human OSM enhanced the mineralization of human muscle-derived stromal cells surrounding NHO (HO-MDSC). OSM was shown to be produced by CD14+ NHO-associated mononuclear cells (HO-mac) when stimulated with LPS, and conditioned media from these cells significantly enhanced HO-MDSC osteogenic potential, an effect that 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 locally produced OSM on muscle cells.

  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.