Neurological heterotopic ossification (NHO) is a frequent complication of spinal cord injuries (SCI). It manifests as abnormal ossification of soft tissues near joints. NHO is debilitating, causing pain, joint deformation, ankylosis and vascular and nerve compression. The mechanisms leading to NHO are poorly defined. As a consequence, the only effective treatment is surgical resection once the NHO become large and debilitating. To elucidate NHO pathophysiology, we have developed the first animal model of NHO following SCI in genetically unmodified mice to model clinical NHO. We have discovered that the combination of a SCI together with muscular inflammation is necessary to initiate NHO, in agreement with clinical observations that NHO are often associated with concomitant infections. We found that macrophages recruited into the inflamed muscle play a critical role in NHO as their depletion in vivo prevents NHO development. Therefore we hypothesise that following SCI, macrophage are abnormally activated in inflamed muscles leading to NHO instead of normal muscle repair. In support of this hypothesis, we find that chemical sympathectomy of peripheral adrenergic nerves significantly reduced NHO in mice with SCI and muscle inflammation. Finally, to better understand the molecular mediators in SCI triggered NHO, we performed mRNA expression profiling of muscles from mice with or without SCI and with or without muscle inflammation. 280 genes were differentially regulated (>2-fold, p<0.005) in muscles from mice with muscle inflammation combined with SCI compared to all other groups. Several of the up-regulated genes encode pro-inflammatory cytokines that activate macrophages including Tnf, Il1b, Ccl2, Csf1 and Osm. We are testing the role of these cytokines by either administering antagonists or using mice knocked-out for the relevant receptors. In conclusion, sympathetic dysfunction as a result of SCI could cause abnormal macrophage activation leading to NHO. This may pave the way to potential pharmacological interventions.