title: Neurological heterotopic ossification following spinal cord injury is triggered by macrophage-mediated inflammation in muscle.
abstract: Neurological heterotopic ossification (NHO) is the abnormal formation of bone in soft tissues as a consequence of spinal cord or traumatic brain injury. NHO causes pain, ankyloses, vascular and nerve compression and delays rehabilitation in this high-morbidity patient group. The pathological mechanisms leading to NHO remain unknown and consequently there are no therapeutic options to prevent or reduce NHO. Genetically modified mouse models of rare genetic forms of heterotopic ossification (HO) exist, but their relevance to NHO is questionable. Consequently, we developed the first model of spinal cord injury (SCI)-induced NHO in genetically unmodified mice. Formation of NHO, measured by micro-computed tomography, required the combination of both SCI and localized muscular inflammation. Our NHO model faithfully reproduced many clinical features of NHO in SCI patients and both human and mouse NHO tissues contained macrophages. Muscle-derived mesenchymal progenitors underwent osteoblast differentiation in vitro in response to serum from NHO mice without additional exogenous osteogenic stimuli. Substance P was identified as a candidate NHO systemic neuropeptide, as it was significantly elevated in the serum of NHO patients. However, antagonism of substance P receptor in our NHO model only modestly reduced the volume of NHO. In contrast, ablation of phagocytic macrophages with clodronate-loaded liposomes reduced the size of NHO by 90%, supporting the conclusion that NHO is highly dependent on inflammation and phagocytic macrophages in soft tissues. Overall, we have developed the first clinically relevant model of NHO and demonstrated that a combined insult of neurological injury and soft tissue inflammation drives NHO pathophysiology.
authors.affiliation: Blood and Bone Diseases Programme, Mater Research Institute, University of Queensland, Woolloongabba, Australia.|Department of Physical Medicine and Rehabilitation, Hôpital Raymond Poincaré, APHP, CIC-IT 1429, Garches, France.|Université Versailles Saint Quentin en Yvelines, END:ICAP U1179 INSERM, UFR des Sciences de la Santé-Simone Veil, Montigny le Bretonneux, France.
authors.forename: François
authors.initials: F
authors.lastname: Genêt
authors.affiliation: Blood and Bone Diseases Programme, Mater Research Institute, University of Queensland, Woolloongabba, Australia.|School of Medicine, University of Queensland, Herston, Australia.
authors.forename: Irina
authors.initials: I
authors.lastname: Kulina
authors.affiliation: Institute of Health Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Australia.
authors.forename: Cedryck
authors.initials: C
authors.lastname: Vaquette
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 972, Villejuif, France.|Université Paris-Sud, Institut André Lwoff, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Torossian
authors.affiliation: Blood and Bone Diseases Programme, Mater Research Institute, University of Queensland, Woolloongabba, Australia.
authors.forename: Susan
authors.initials: S
authors.lastname: Millard
authors.affiliation: Blood and Bone Diseases Programme, Mater Research Institute, University of Queensland, Woolloongabba, Australia.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Pettit
authors.affiliation: St Vincent's Institute of Medical Research, Fitzroy, Australia.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 972, Villejuif, France.|Université Paris-Sud, Institut André Lwoff, Paris, France.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Anginot
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 972, Villejuif, France.|Université Paris-Sud, Institut André Lwoff, Paris, France.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Guerton
authors.affiliation: Blood and Bone Diseases Programme, Mater Research Institute, University of Queensland, Woolloongabba, Australia.
authors.forename: Ingrid G
authors.initials: IG
authors.lastname: Winkler
authors.affiliation: Blood and Bone Diseases Programme, Mater Research Institute, University of Queensland, Woolloongabba, Australia.
authors.forename: Valérie
authors.initials: V
authors.lastname: Barbier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 972, Villejuif, France.|Centre de Transfusion Sanguine des Armées, Clamart, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lataillade
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 972, Villejuif, France.|Université Paris-Sud, Institut André Lwoff, Paris, France.
authors.forename: Marie-Caroline
authors.initials: MC
authors.lastname: Le Bousse-Kerdilès
authors.affiliation: Blood and Bone Diseases Programme, Mater Research Institute, University of Queensland, Woolloongabba, Australia.
authors.forename: Dietmar W
authors.initials: DW
authors.lastname: Hutmacher
authors.affiliation: Blood and Bone Diseases Programme, Mater Research Institute, University of Queensland, Woolloongabba, Australia.|School of Medicine, University of Queensland, Herston, Australia.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Levesque
mesh_terms: D000818:Animals; D054715:Cardiotoxins / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D009220:Myositis / Q000209:etiology*; D009999:Ossification, Heterotopic / Q000209:etiology*; D010264:Paraplegia / Q000150:complications; D013119:Spinal Cord Injuries / Q000150:complications*; D013234:Stem Cells / Q000502:physiology
chemical_list: D054715:Cardiotoxins
keywords: heterotopic ossification; inflammation; macrophage; spinal cord injury