Estrogen receptor-α ablation reverses muscle fibrosis and inguinal hernias
Tanvi Potluri, … , Hong Zhao, Serdar E. Bulun
Tanvi Potluri, … , Hong Zhao, Serdar E. Bulun
Published February 4, 2025
Citation Information: J Clin Invest. 2025;135(6):e179137. https://doi.org/10.1172/JCI179137.
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Research Article Cell biology Muscle biology Reproductive biology

Estrogen receptor-α ablation reverses muscle fibrosis and inguinal hernias

Abstract

Fibrosis of the lower abdominal muscle (LAM) contributes to muscle weakening and inguinal hernia formation, an ailment that affects a noteworthy 50% of men by age 75 and necessitates surgical correction as the singular therapy. Despite its prevalence, the mechanisms driving LAM fibrosis and hernia development remain poorly understood. Using a humanized mouse model that replicates the elevated skeletal muscle tissue estrogen concentrations seen in aging men, we identified estrogen receptor-α (ESR1) as a key driver of LAM fibroblast proliferation, extracellular matrix deposition, and hernia formation. Fibroblast-specific ESR1 ablation effectively prevented muscle fibrosis and herniation, while pharmacological ESR1 inhibition with fulvestrant reversed hernias and restored normal muscle architecture. Multiomics analyses of in vitro LAM fibroblasts from humanized mice unveiled an estrogen/ESR1-mediated activation of a distinct profibrotic cistrome and gene expression signature, concordant with observations in inguinal hernia tissues in human males. Our findings hold significant promise for prospective medical interventions targeting fibrotic conditions and present non-surgical avenues for addressing inguinal hernias.

Authors

Tanvi Potluri, Tianming You, Ping Yin, John Coon V, Jonah J. Stulberg, Yang Dai, David J. Escobar, Richard L. Lieber, Hong Zhao, Serdar E. Bulun

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Figure 1

Fibroblast-specific ablation of ESR1 in Aromhum mice prevents herniation.

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Fibroblast-specific ablation of ESR1 in Aromhum mice prevents herniation...
(A) Representative images of WT and Aromhum mice, and an illustration depicting scrotal hernia and LAMs. Created with BioRender (biorender.com). (B) Measurement of scrotal hernia size with age in fibroblast-specific Esr1-knockout mice (fEsr1–/– Aromhum) and fEsr1+/+ Aromhum and fEsr1+/+ WT littermate controls (n = 3–4 per group, mean ± SEM, repeated-measures ANOVA with Bonferroni multiple comparisons). (C) Flow cytometry dot plots showing the percentage of PDGFRA+ estrogen receptor-α–positive HAFs in LAMs from fEsr1–/– Aromhum and control fEsr1+/+ Aromhum mice (n = 3). (D) Representative images of scrotal hernias (top) and Masson’s trichrome–stained LAMs (bottom). Red arrows point to scrotal hernia, while yellow arrows point to atrophied myofibers. Scale bars: 100 μm. (E) Quantification of the fibrotic area in fEsr1–/– Aromhum, fEsr1+/+ Aromhum, and fEsr1+/+ WT mice (n = 3–4 per group, median ± interquartile range, 1-way ANOVA with Bonferroni multiple comparisons).