Metallopeptidades 2 and 9 genes epigenetically modulate equine endometrial fibrosis.
Authors: Alpoim-Moreira Joana, Fernandes Carina, Pimenta Jorge, Bliebernicht Miguel, Rebordão Maria Rosa, Castelo-Branco Pedro, Szóstek-Mioduchowska Anna, Skarzynski Dariusz J, Ferreira-Dias Graça
Journal: Frontiers in veterinary science
Summary
# Editorial Summary: Epigenetic Control of Endometrosis in Mares Endometrosis—characterised by collagen accumulation and periglandular fibrosis—represents a significant cause of subfertility in mares, yet its underlying mechanisms remain incompletely understood. This Portuguese-led research team investigated whether epigenetic modifications, specifically DNA methylation patterns, regulate genes controlling collagen turnover in affected endometria, using 24 endometrial biopsies classified across the Kenney and Doig grading system (6 samples per category) and measuring both transcription levels and methylation status of key genes. The critical finding was that MMP-2 and MMP-9 genes showed progressive hypermethylation in severely fibrotic tissue (category III), with methylation levels inversely correlated to their mRNA expression; simultaneously, TIMP-1 transcripts increased in fibrotic samples, creating an unfavourable balance in the protease-to-inhibitor ratio that perpetuates collagen deposition. Notably, the pathology appears driven by silencing of anti-fibrotic metalloproteinases rather than activation of fibrotic genes—a distinction with therapeutic significance, since epigenetic modifications are potentially reversible through targeted interventions. For practitioners, this suggests that future treatments targeting DNA methylation patterns, rather than attempting to suppress collagen synthesis directly, may offer a more physiologically aligned approach to managing endometrosis and improving reproductive outcomes in affected mares.
Read the full abstract on PubMed
Practical Takeaways
- •Endometrosis involves reversible epigenetic changes that silence anti-fibrotic genes, offering potential for novel therapeutic interventions targeting DNA methylation rather than permanent genetic changes
- •MMP2 and MMP9 inhibition appears to be a key mechanism in endometrial fibrosis development, suggesting these genes could be therapeutic targets to restore mare fertility
- •Endometrial biopsy histological grading correlates with specific molecular changes, supporting its continued use for characterizing endometrosis severity and predicting treatment responsiveness
Key Findings
- •MMP2 and MMP9 transcripts decreased significantly with endometrial fibrosis progression compared to healthy endometrium (P < 0.05)
- •Hypermethylation of MMP2 and MMP9 genes occurred in severely fibrotic endometrium (category III) and correlated with decreased mRNA expression (P < 0.001 and P < 0.05 respectively)
- •TIMP1 transcripts were elevated in severe fibrosis (category III) compared to normal endometrium (P < 0.05)
- •Endometrosis appears epigenetically modulated through repression of anti-fibrotic genes (MMP2/MMP9) rather than activation of pro-fibrotic genes