Ethan A. Noyola

Background: By broadly suppressing inflammatory gene programs through the intracellular glucocorticoid receptor (GR), glucocorticoids remain among the most clinically powerful anti-inflammatory drugs available.¹,² Glucocorticoids delay disease progression and prolong ambulation, but not without a cost as chronic exposure contributes to growth suppression, muscle wasting, osteoporosis, metabolic dysregulation, and adrenal suppression. In Duchenne muscular dystrophy (DMD), this efficacy-to-toxicity tradeoff is particularly hard to ignore.³,⁴ In attempts to understand their mechanism, the classic “dissociation” model was proposed and suggested that the anti-inflammatory benefit of glucocorticoids arises primarily from monomeric GR tethering to transcription factors such as NF-κB and AP-1, whereas their toxic effects result from GR dimerization and glucocorticoid response element-mediated transactivation.⁵ This model encouraged the development of “safer steroids” to minimize GR dimerization or DNA binding. However, recent mechanistic evidence challenges this classic model and whether anti-inflammatory efficacy can truly be separated from GR’s genomic activity.

Objective: This narrative review challenges the classic monomer-dimer dissociation model as an incomplete explanation for glucocorticoids efficacy and toxicity, under the context of DMD, and reframes safer glucocorticoid therapy around selective GR transcriptional reprogramming.

Search Methods: PubMed and Google Scholar were searched for studies published from 2019 to 2026 using the keywords and MeSH-related terms “glucocorticoid receptor,” “glucocorticoids,” “Duchenne muscular dystrophy,” “GR dimerization,” “GR monomer,” “transrepression,” “DNA binding,” “inflammation,” and “steroid toxicity.” Primary mechanistic studies, reviews, and clinical trials most directly relevant to GR signaling and DMD therapy were prioritized.

Results: Current evidence indicates that GR anti-inflammatory repression is not simply a DNA-independent tethering process. Using a GR zinc-finger mutant retaining protein-protein interactions but defective in DNA recognition, Escoter-Torres et al demonstrated that loss of proper DNA binding impaired both activation and repression of inflammatory-response genes. This supports the notion that DNA binding is necessary for anti-inflammatory GR functions.⁶ Further, genome-wide analysis by Johnson et al added to this support by showing that monomeric GR activity alone is insufficient for broad transcriptional regulation. GRdim, a partial dimerization-defective mutant, retained limited chromatin binding with regulatory function, whereas GRmon, a fully monomeric mutant, was nearly nonfunctional, impairing both activation and repression when compared with wild-type GR.⁷ In DMD, Howard et al showed inflammation to not be merely secondary to muscle damage as inflammatory signaling and chemokine/cytokine burden rise with dystrophic severity, making inflammatory control mechanistically critical to the progression of disease.⁸ Moreover, Oliver et al revealed that GR deletion in myofiber and cardiomyocytes in dystrophic mice worsened skeletal muscle strength, inflammatory pathology, cardiomyopathy, along with ejection fraction. These findings support a locally protective role for endogenous GR in dystrophic muscle and heart.⁹ Preclinical work suggests that vamorolone may reduce inflammation and dystrophic pathology through altered nuclear receptor signaling rather than simple GR weakening.¹⁰ Clinically, this concept is supported by a randomized trial in which, when compared to placebo, vamorolone improved time-to-stand and 6-minute walk outcomes and produced less height-percentile decline with more favorable bone biomarkers than prednisone, although adrenal insufficiency remained a limitation.⁴

Conclusions: The classic monomer-versus-dimer model is too simplistic because anti-inflammatory GR activity requires genomic engagement, and in DMD, local GR signaling appears essential for protecting dystrophic muscle and heart. By indiscriminately weakening GR DNA binding, protective programs in dystrophic muscle and heart could be undermined and potentially accelerate disease progression. Future glucocorticoid development should be guided by selective GR reprogramming and aim to preserve both anti-inflammatory and tissue-protective transcriptional outputs while minimizing systemic toxicity through chromatin occupancy, tissue specific signaling and cofactor recruitment.

Works Cited:

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4.  Guglieri M, Clemens PR, Perlman SJ, et al. Efficacy and safety of vamorolone vs placebo and prednisone among boys with Duchenne muscular dystrophy: a randomized clinical trial. JAMA Neurol. 2022;79(10):1005-1014. doi:10.1001/jamaneurol.2022.2480
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8. Howard ZM, Lowe J, Blatnik AJ 3rd, et al. Early inflammation in muscular dystrophy differs between limb and respiratory muscles and increases with dystrophic severity. Am J Pathol. 2021;191(4):730-747. doi:10.1016/j.ajpath.2021.01.008
9.  Oliver T, Nguyen NY, Tully CB, et al. The glucocorticoid receptor acts locally to protect dystrophic muscle and heart during disease. Dis Model Mech. 2024;17(5):dmm050397. doi:10.1242/dmm.050397
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