When the Nervous System Turns Skeletal Muscles into Bones: How to Solve the Conundrum of Neurogenic Heterotopic Ossifica
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SKELETAL BIOLOGY AND REGULATION (MR FORWOOD AND A ROBLING, SECTION EDITORS)
When the Nervous System Turns Skeletal Muscles into Bones: How to Solve the Conundrum of Neurogenic Heterotopic Ossification Kylie A. Alexander 1 & Hsu-Wen Tseng 1 & Marjorie Salga 2,3 & François Genêt 2,3 & Jean-Pierre Levesque 1 Accepted: 9 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose of Review Neurogenic heterotopic ossification (NHO) is the abnormal formation of extra-skeletal bones in periarticular muscles after damage to the central nervous system (CNS) such as spinal cord injury (SCI), traumatic brain injury (TBI), stroke, or cerebral anoxia. The purpose of this review is to summarize recent developments in the understanding of NHO pathophysiology and pathogenesis. Recent animal models of NHO and recent findings investigating the communication between CNS injury, tissue inflammation, and upcoming NHO therapeutics are discussed. Recent Findings Animal models of NHO following TBI or SCI have shown that NHO requires the combined effects of a severe CNS injury and soft tissue damage, in particular muscular inflammation and the infiltration of macrophages into damaged muscles plays a key role. In the context of a CNS injury, the inflammatory response to soft tissue damage is exaggerated and persistent with excessive signaling via substance P-, oncostatin M-, and TGF-β1-mediated pathways. Summary This review provides an overview of the known animal models and mechanisms of NHO and current therapeutic interventions for NHO patients. While some of the inflammatory mechanisms leading to NHO are common with other forms of traumatic and genetic heterotopic ossifications (HO), NHOs uniquely involve systemic changes in response to CNS injury. Future research into these CNS-mediated mechanisms is likely to reveal new targetable pathways to prevent NHO development in patients. Keywords Neurogenic heterotopic ossification . Inflammation . Cytokines . Macrophages . Central nervous system
Introduction Neurogenic heterotopic ossifications (NHOs) are abnormal extra-skeletal bone formations mostly in periarticular muscles [1] after severe damage to the central nervous system (CNS) This article is part of the Topical Collection on Skeletal Biology and Regulation * Jean-Pierre Levesque [email protected] 1
Mater Research Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland 4102, Australia
2
Department of Physical Medicine and Rehabilitation, CIC 1429, Raymond Poincaré Hospital, APHP, Garches, France
3
END:ICAP U1179 INSERM, University of Versailles Saint Quentin en Yvelines, UFR Simone Veil-Santé, Montigny le Bretonneux, France
such as spinal cord injury (SCI), traumatic brain injury (TBI), stroke, or cerebral anoxia [2] and hence their name “neurogenic.” NHOs were first identified in spine-injured soldiers during World War I with the first use of radiography in battlefield injuries [3–5] and are still very preval
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