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

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2024-12-17 Epub Date: 2024-12-09 DOI:10.1016/j.xcrm.2024.101849

Kylie A Alexander, Hsu-Wen Tseng, Hong Wa Lao, Dorothée Girard, Valérie Barbier, Jacobus P J Ungerer, Brett C McWhinney, Selwin G Samuel, Whitney Fleming, Ingrid G Winkler, Marjorie Salga, François Genêt, Sébastien Banzet, Marc J Ruitenberg, Jean-Pierre Lévesque

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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.

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脊髓损伤后异位骨化的糖皮质激素突刺修复。

为什么中枢神经系统（CNS）的严重损伤会引发关节周围肌肉内大神经源性异位骨化（NHOs）的发展尚不清楚。我们报道脊髓损伤（SCI）在小鼠中触发皮质酮快速峰值，这是NHO发展的原因，因为皮质酮或合成糖皮质激素（GC）受体（GR）激动剂地塞米松治疗足以触发异位骨化，并上调受伤肌肉中成骨诱导和成骨分化基因的表达，即使没有SCI。在GR基因（Nr3c1）缺失的小鼠中进一步证实了GR信号在引起NHO中的核心作用，这些小鼠在脊髓损伤后不再发生NHO。此外，给药临床GR拮抗剂可抑制脊髓损伤小鼠NHO的发展。本研究确定内源性GC可引起CNS损伤后的病理性NHO，并提示GR拮抗剂可用于预防严重CNS损伤患者NHO的发生。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.