2. Academic Validation
  3. A glucocorticoid spike derails muscle repair to heterotopic ossification after spinal cord injury

A glucocorticoid spike derails muscle repair to heterotopic ossification after spinal cord injury

  • Cell Rep Med. 2024 Dec 17;5(12):101849. doi: 10.1016/j.xcrm.2024.101849.
Kylie A Alexander 1,  Hsu-Wen Tseng 2,  Hong Wa Lao 3,  Dorothée Girard 4,  Valérie Barbier 2,  Jacobus P J Ungerer 5,  Brett C McWhinney 6,  Selwin G Samuel 2,  Whitney Fleming 2,  Ingrid G Winkler 2,  Marjorie Salga 7,  François Genêt 8,  Sébastien Banzet 4,  Marc J Ruitenberg 3,  Jean-Pierre Lévesque 9
Affiliations

Affiliations

  • 1 Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia. Electronic address: kylie.alexander@mater.uq.edu.au.
  • 2 Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
  • 3 School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD 4067, Australia.
  • 4 Institut de Recherche Biomédicale des Armées, 92140 Clamart, France; INSERM, UMR-MD U1197 SToRM, 92140 Clamart, France.
  • 5 School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD 4067, Australia; Department of Chemical Pathology, Pathology Queensland, Herston, QLD 4029, Australia.
  • 6 Department of Chemical Pathology, Pathology Queensland, Herston, QLD 4029, Australia.
  • 7 Unité Péri-Opératoire du Handicap, Physical and Rehabilitation Medicine Department, Hôpital Raymond-Poincaré, Assistance Publique Hôpitaux de Paris (APHP), 92380 Garches, France.
  • 8 Unité Péri-Opératoire du Handicap, Physical and Rehabilitation Medicine Department, Hôpital Raymond-Poincaré, Assistance Publique Hôpitaux de Paris (APHP), 92380 Garches, France; Université Versailles Saint-Quentin-en-Yvelines, UFR Simone Veil - Santé, END:ICAP, INSERM U1179, 78180 Montigny-le-Bretonneux, France.
  • 9 Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia. Electronic address: jp.levesque@mater.uq.edu.au.
PMID: 39657663 DOI: 10.1016/j.xcrm.2024.101849
Abstract

Why severe injury to the central nervous system (CNS) triggers the development of large neurogenic heterotopic ossifications (NHOs) within periarticular muscles remains unknown. We report that spinal cord injury (SCI) triggers a rapid corticosterone spike in mice, which is causal for NHO development because treatments with corticosterone or the synthetic glucocorticoid (GC) receptor (GR) agonist dexamethasone are sufficient to trigger heterotopic ossification and upregulate the expression of osteoinductive and osteogenic differentiation genes in injured muscles even without SCI. The central role for GR signaling in causing NHO is further demonstrated in mice deleted for the GR gene (Nr3c1), which no longer develop NHO after SCI. Furthermore, administration of clinical GR antagonists inhibits NHO development in mice with SCI. This study identifies endogenous GC as causing pathological NHO after CNS injury and suggests that GR antagonists may be of prophylactic use to prevent NHO development in victims of severe CNS injuries.

Keywords

Glucocorticoid receptor; dexamethasone; fibroadipogenic progenitor; inflammation; mifepristone; muscle repair; neurogenic heterotopic ossification; osteoblast; relacorilant; spinal cord injury.

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