Steroids and Bones: How Glucocorticoids Hijack Muscle Repair After Spinal Cord Injury

The Mystery of Misguided Healing

Severe spinal cord injury (SCI) does more than disrupt neural pathways; it sets off a cascade of unexpected biological processes. Among these is neurogenic heterotopic ossification (NHO), the abnormal formation of bone in soft tissues like muscles. This condition exacerbates the challenges of recovery, causing pain, joint immobility, and often requiring invasive surgical intervention. While its clinical implications are well-documented, the underlying mechanisms have long remained a mystery.

Recent research sheds light on the molecular drivers of NHO, implicating glucocorticoids (GCs)—hormones secreted by the adrenal glands during stress—as a critical factor. The study finds that SCI triggers a spike in GC levels, which corrupts normal muscle repair processes and promotes pathological bone formation. These findings mark a turning point in understanding NHO and point toward new therapeutic possibilities.

The significance of this research extends beyond SCI. GCs, often used as anti-inflammatory agents in clinical settings, may have unexpected pro-inflammatory effects in specific contexts. This duality complicates their therapeutic use, underscoring the need for precision medicine approaches in treating injuries and related complications.

The Corticosteroid Surge: A Trigger for Bone Growth

Within 24 hours of SCI, rodents exhibit a significant surge in corticosterone, the primary glucocorticoid in mice. Unlike the modest hormonal changes associated with isolated muscle injuries, SCI induces a robust corticosterone spike. This suggests a central role for systemic stress responses in driving NHO formation. Remarkably, corticosterone levels return to baseline after 48 hours, underscoring a narrow therapeutic window for intervention.

The study further demonstrates that administering corticosterone to non-SCI mice with muscle injuries is sufficient to induce NHO. This effect is dose-dependent and timing-sensitive: only early and sustained exposure to corticosterone drives ossification. This finding illustrates how GCs transform the local muscle environment, priming it for pathological bone formation in response to injury.

Importantly, the researchers also tested dexamethasone, a synthetic glucocorticoid commonly used in medicine. Like corticosterone, dexamethasone triggered NHO when administered during the critical early phase of muscle injury. This raises concerns about the widespread clinical use of GCs in managing acute injuries and underscores the need for careful reconsideration of their role in trauma care.

Cellular Pathways: How Muscle Repair Becomes Bone Formation

Under normal circumstances, muscle repair involves a collaborative effort between satellite cells (SCs) and fibro-adipogenic progenitors (FAPs). SCs regenerate damaged muscle fibers, while FAPs provide structural support before undergoing programmed cell death (apoptosis). This balance ensures effective healing without scarring or fibrosis. However, SCI derails this process by preventing FAP apoptosis, allowing these cells to persist and differentiate abnormally.

SCI-induced glucocorticoids exacerbate this dysfunction by activating osteogenic pathways within injured muscles. The expression of key genes, such as Runx2 and Sox11, shifts FAPs from a supportive role toward osteoblast differentiation. Meanwhile, inflammatory cytokines, including IL-1β and oncostatin M (OSM), further skew the muscle environment, creating a fertile ground for bone formation.

Interestingly, the study highlights a temporal component to this phenomenon. The window for FAP misdirection is narrow, correlating with the initial spike in GC levels post-SCI. Once this period passes, the likelihood of NHO formation decreases, suggesting potential opportunities for intervention to restore normal repair mechanisms.

Genetic Evidence: The Glucocorticoid Receptor as the Key Player

To probe the role of glucocorticoid signaling, researchers used genetically modified mice lacking the Nr3c1 gene, which encodes the glucocorticoid receptor (GR). These mice, when subjected to SCI and muscle injury, failed to develop NHO. This result strongly implicates GR-mediated signaling as a necessary driver of pathological ossification.

In addition to genetic models, pharmacological interventions with GR antagonists yielded similarly compelling results. Mice treated with mifepristone, a dual GR and progesterone receptor antagonist, showed significantly reduced NHO volumes. Notably, the efficacy of this treatment was time-sensitive, with the first 48 hours post-SCI emerging as the critical window for intervention.

Further experiments demonstrated that GR antagonists like relacorilant—a more selective inhibitor—could achieve comparable outcomes without affecting progesterone pathways. These findings not only validate the role of GR in NHO pathogenesis but also identify it as a promising therapeutic target for prophylactic treatment in SCI patients.

Revisiting Glucocorticoids: From Anti-Inflammatory to Pro-Inflammatory

Glucocorticoids have long been celebrated for their anti-inflammatory properties, widely used in managing autoimmune diseases, allergies, and acute injuries. However, the study reveals a startling paradox: in the context of hypoxic muscle injuries, GCs can act as pro-inflammatory agents. Instead of suppressing inflammation, they amplify cytokine activity, exacerbating tissue damage and promoting ossification.

This pro-inflammatory effect is particularly pronounced in the presence of SCI, where elevated GC levels coincide with increased expression of IL-1β, OSM, and their receptors. These molecules play a critical role in activating the JAK/STAT3 signaling pathway, a key driver of both inflammation and osteogenesis in injured tissues.

The findings challenge conventional assumptions about GC therapy, particularly in trauma care. While GCs may mitigate neuroinflammation in the spinal cord, their broader systemic effects could inadvertently worsen complications like NHO. This highlights the importance of context-specific approaches in GC use, balancing their benefits against potential risks.

Translating Insights to Human Patients: Clinical Implications

The translational relevance of these findings is underscored by experiments using human muscle progenitor cells (MPCs) isolated from NHO biopsies. When exposed to cortisol, the human equivalent of corticosterone, these cells exhibited enhanced mineralization, mimicking the ossification observed in animal models. This consistency across species validates the central role of GCs in driving pathological bone formation.

Retrospective studies further support these findings, linking high cortisol levels in SCI patients to an increased risk of NHO. This correlation emphasizes the potential for early GC modulation as a preventive strategy. However, the study also notes that existing clinical practices, such as administering methylprednisolone to reduce spinal cord swelling, may inadvertently heighten the risk of NHO.

Looking forward, the development of selective GR antagonists offers a promising avenue for clinical application. By targeting the specific pathways involved in NHO without disrupting overall muscle repair or systemic hormone balance, these therapies could transform the management of SCI complications.

Charting a New Course for SCI Treatment

This research fundamentally alters our understanding of glucocorticoids in injury recovery, revealing their capacity to disrupt normal muscle repair and drive pathological ossification. By elucidating the mechanisms behind GC-driven NHO, the study opens the door to novel prophylactic treatments that could spare SCI patients from invasive surgeries and chronic disability.

As medicine moves toward precision approaches, the role of glucocorticoids in trauma care warrants careful reconsideration. Balancing their benefits in controlling inflammation with their potential to exacerbate conditions like NHO will require not only new drugs but also a shift in clinical paradigms. The findings highlight the promise of GR antagonists as a targeted intervention, offering hope for improved outcomes in one of the most challenging complications of SCI.

Study DOI: https://doi.org/10.1016/j.xcrm.2024.101849

Engr. Dex Marco Tiu Guibelondo, B.Sc. Pharm, R.Ph., B.Sc. CpE

Editor-in-Chief, PharmaFEATURES