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

Neuro-immune 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 multistep process that creates an osteo-permissive 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.