biostudies-literatureAlexander KAUniversity of QueenslandWings for Life Spinal Cord Research FoundationWings for LifeMater FoundationSpinalCure AustraliaNational Health and Medical Research CouncilUS Department of Defense101849https://www.ebi.ac.uk/biostudies/studies/S-EPMC11722129biostudies-literatureUnknown5(12)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 inhibiCell reports. MedicineA glucocorticoid spike derails muscle repair to heterotopic ossification after spinal cord injury.PMC117221291163835W81XWH2110560W81XWH-15-1-0606WFL-AU-19/171181053Samuel SGWinkler IGSalga MBanzet SMcWhinney BCFleming WLao HWLevesque JPGirard DBarbier VGenet FTseng HWAlexander KARuitenberg MJUngerer JPJfalseA glucocorticoid spike derails muscle repair to heterotopic ossification after spinal cord injury.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 inhibi2024-01-01T00:00:00Z2024 Dec2026-06-01T15:08:43.911Z2026-04-08T13:36:07.306ZS-EPMC117221293965766310.1016/j.xcrm.2024.101849