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

Cell Reports Medicine, 2024 · DOI: https://doi.org/10.1016/j.xcrm.2024.101849 · Published: December 17, 2024

Spinal Cord Injury Endocrinology Musculoskeletal Medicine

Simple Explanation

Severe spinal cord injuries (SCIs) can lead to the formation of heterotopic ossifications (NHOs) in muscles. This study reveals that a spike in corticosterone, a glucocorticoid (GC), following SCI is a key cause of NHO development. Treatments with glucocorticoid receptor antagonists or deletion of the receptor gene in mice inhibits NHO formation after SCI. This suggests that blocking GC signaling could prevent NHO development in individuals with severe CNS injuries. The study identifies increased adrenal glucocorticoids (GCs) in the blood in response to SCI as a targetable trigger of NHO development.

Study Duration

1-3 weeks

Participants

Mice (C57BL/6, BALB/c, Nr3c1 conditional knock-out mice) and human NHO biopsy samples from 5 patients (4 males, 1 female)

Evidence Level

Not specified

Key Findings

1
Severe SCI causes a spike in blood corticosterone in mice, which is causal for NHO development.
2
Treatment with GC triggers heterotopic ossiﬁcations in injured muscles in mice, even without SCI.
3
Post-natal deletion of the GR gene in mice prevents NHO development after SCI, demonstrating the central role for GR signaling.

Research Summary

This study investigates why severe injury to the central nervous system (CNS) triggers the development of large neurogenic heterotopic ossiﬁcations (NHOs) within periarticular muscles. 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. 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.

Practical Implications

Prophylactic Treatment

GR antagonists may offer a prophylactic treatment to prevent NHO development in victims of severe CNS injuries.

Caution with GR Agonists

Acute anti-inflammatory treatments with GR agonists should be avoided in victims of CNS injuries, as they may drive or exacerbate NHO development.

Steroid Neuro-Endocrine Mediators

Steroid neuro-endocrine mediators play a key role in orchestrating tissue-specific stem cell proliferation and differentiation during tissue repair.

Study Limitations

1
Lack of prospective correlative study to demonstrate a signiﬁcant association between high blood cortisol in acute phase following SCI and subsequent NHO development in patients.
2
Safety profile of GR antagonists has not been established in victims of SCI.
3
Whether endogenous GCs were similarly involved in the pathogenesis of NHO following TBI was not tested.

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