Local and systemic factors drive ectopic osteogenesis in regenerating muscles of spinal-cord-injured mice in a lesion-level-dependent manner

International audienceNeuroimmune dysfunction is thought to promote the development of several acute and chronic complications in spinal cord injury (SCI) patients. Putative roles for adrenal stress hormones and catecholamines are increasingly being recognized, yet how these adversely affect peripheral tissue homeostasis and repair under SCI conditions remains elusive. Here, we investigated their influence in a mouse model of SCI with acquired neurogenic heterotopic ossification. We show that spinal cord lesions differentially influence muscular regeneration in a level-dependent manner and through a complex multi-step process that creates an osteopermissive environment within the first hours of injury. This cascade of events is shown to critically involve adrenergic signals and drive the acute release of the neuropeptide, substance P. Our findings generate new insights into the kinetics and processes that govern SCI-induced deregulations in skeletal muscle homeostasis and regeneration, thereby aiding the development of sequential therapeutic strategies that can prevent or attenuate neuromusculoskeletal complications in SCI patients

Neurogenic heterotopic ossifications develop independently of granulocyte‐colony stimulating factor and neutrophils

Neurogenic heterotopic ossifications (NHO) are incapacitating heterotopic bones in periarticular muscles that frequently develop following traumatic brain or spinal cord injuries (SCI). Using our unique model of SCI-induced NHO, we have previously established that mononucleated phagocytes infiltrating injured muscles are required to trigger NHO via the persistent release of the pro-inflammatory cytokine oncostatin M (OSM). As neutrophils are also a major source of OSM, we investigated whether neutrophils also play a role in NHO development after SCI. We now demonstrate that surgery transiently increased granulocyte colony stimulating factor (G-CSF) levels in blood of operated mice, and that G-CSF receptor mRNA is expressed in the hamstrings of mice developing NHO. However, mice defective for the G-CSF receptor gene Csf3r, which are neutropenic, have unaltered NHO development after SCI compared to C57Bl/6 control mice. As the administration of recombinant human G-CSF (rhG-CSF) has been trialed after SCI to increase neuroprotection and neuronal regeneration and has been shown to suppress osteoblast function at the endosteum of skeletal bones in human and mice, we investigated the impact of a seven-day rhG-CSF treatment on NHO development. rhG-CSF treatment significantly increased neutrophils in the blood, bone marrow and injured muscles. However, there was no change in NHO development compared to saline treated controls. Overall, our results establish that unlike monocytes / macrophages, neutrophils are dispensable for NHO development following SCI and rhG-CSF treatment post-SCI does not impact NHO development. Therefore, G-CSF treatment to promote neuro-regeneration is unlikely to adversely promote or affect NHO development in SCI patients. This article is protected by copyright. All rights reserved

Inhibition of JAK1/2 Tyrosine Kinases Reduces Neurogenic Heterotopic Ossification After Spinal Cord Injury

Neurogenic heterotopic ossifications (NHO) are very incapacitating complications of traumatic brain and spinal cord injuries (SCI) which manifest as abnormal formation of bone tissue in periarticular muscles. NHO are debilitating as they cause pain, partial or total joint ankylosis and vascular and nerve compression. NHO pathogenesis is unknown and the only effective treatment remains surgical resection, however once resected, NHO can re-occur. To further understand NHO pathogenesis, we developed the first animal model of NHO following SCI in genetically unmodified mice, which mimics most clinical features of NHO in patients. We have previously shown that the combination of (1) a central nervous system lesion (SCI) and (2) muscular damage (via an intramuscular injection of cardiotoxin) is required for NHO development. Furthermore, macrophages within the injured muscle play a critical role in driving NHO pathogenesis. More recently we demonstrated that macrophage-derived oncostatin M (OSM) is a key mediator of both human and mouse NHO. We now report that inflammatory monocytes infiltrate the injured muscles of SCI mice developing NHO at significantly higher levels compared to mice without SCI. Muscle infiltrating monocytes and neutrophils expressed OSM whereas mouse muscle satellite and interstitial cell expressed the OSM receptor (OSMR). In vitro recombinant mouse OSM induced tyrosine phosphorylation of the transcription factor STAT3, a downstream target of OSMR:gp130 signaling in muscle progenitor cells. As STAT3 is tyrosine phosphorylated by JAK1/2 tyrosine kinases downstream of OSMR:gp130, we demonstrated that the JAK1/2 tyrosine kinase inhibitor ruxolitinib blocked OSM driven STAT3 tyrosine phosphorylation in mouse muscle progenitor cells. We further demonstrated in vivo that STAT3 tyrosine phosphorylation was not only significantly higher but persisted for a longer duration in injured muscles of SCI mice developing NHO compared to mice with muscle injury without SCI. Finally, administration of ruxolitinib for 7 days post-surgery significantly reduced STAT3 phosphorylation in injured muscles in vivo as well as NHO volume at all analyzed time-points up to 3 weeks post-surgery. Our results identify the JAK/STAT3 signaling pathway as a potential therapeutic target to reduce NHO development following SCI

L’autel-reliquaire de Sainte-Marie de l’Aventin à Rome, exemple de la “renovatio” clunisienne

Nella chiesa di S. Maria in Aventino a Roma, si trova un altare reliquario relativamente raro per quanto riguarda la decorazione e le iscrizioni. Le datazioni proposte dagli storici vanno dal VI secolo a XII secolo. Applicando un metodologia comparata basata sulla storia, la storia dell'arte, la paleografia e l'epigrafia, si giunge alla conclusione che l'altare risale al secolo X, o al principio del secolo XI. Esso presenta un gran numero di elementi grafici ed ornamentali ispirati all'antichità classica. Realizzato per un monastero cluniacense a Roma, l'altare rappresenta la tendenza dell'ordine cluniacense a volersi ispirare alla Roma dell'inizio del Cristianesimo, dimostrando al contempo, l'importanza dell'ideale di "renovatio" nella produzione artistica dell'epoca

Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications

International audienc

Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications

International audienc