Alexander Kylie A, Tseng Hsu-Wen, Lao Hong Wa, Girard Dorothée, Barbier Valérie, Ungerer Jacobus P J, McWhinney Brett C, Samuel Selwin G, Fleming Whitney, Winkler Ingrid G, Salga Marjorie, Genêt François, Banzet Sébastien, Ruitenberg Marc J, Lévesque Jean-Pierre
Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
Cell Rep Med. 2024 Dec 17;5(12):101849. doi: 10.1016/j.xcrm.2024.101849. Epub 2024 Dec 9.
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.
中枢神经系统（CNS）受到严重损伤后，为何会在关节周围肌肉内引发大型神经源性异位骨化（NHOs），目前尚不清楚。我们报告称，脊髓损伤（SCI）会引发小鼠体内皮质酮迅速飙升，这是NHO形成的原因，因为使用皮质酮或合成糖皮质激素（GC）受体（GR）激动剂地塞米松进行治疗，即便没有SCI，也足以引发异位骨化，并上调受伤肌肉中骨诱导和成骨分化基因的表达。在GR基因（Nr3c1）缺失的小鼠中，进一步证明了GR信号在导致NHO方面的核心作用，这些小鼠在SCI后不再发生NHO。此外，给予临床GR拮抗剂可抑制SCI小鼠的NHO形成。本研究确定内源性GC是中枢神经系统损伤后导致病理性NHO的原因，并表明GR拮抗剂可能具有预防作用，可防止严重中枢神经系统损伤患者发生NHO。
