The MEG3-miRNA regulatory axis could potentially modulate response to biological therapies in psoriatic arthritis.

Abstract

Background: The long non-coding RNA - microRNA (lncRNA-miRNA) regulatory axis is a key modulator of immune and inflammatory pathways, and growing evidence supports its contribution to therapeutic response variability. In our previous study, we identified the lncRNA MEG3 as potentially involved in the response to biological drugs, specifically TNFα- and IL17A-inhibitors, in psoriatic arthritis (PsA).

Methods: To further characterize its role, we performed a bioinformatic analysis to identify MEG3-targeted miRNAs, followed by an exploratory expression profiling analysis using qRT-PCR in a cohort of 54 PsA patients at baseline (T0) and after 12 months of therapy (T12), compared with 15 healthy controls (CTRLs).

Result: We identified four candidate miRNA targets: hsa-miR-21-5p, hsa-miR-19b-3p, hsa-miR-19a-3p, and hsa-miR-17-5p. Among these, hsa-miR-17-5p was significantly upregulated in PsA patients at T0 versus CTRLs. Most importantly, we found a significant decrease in hsa-miR-17-5p and hsa-miR-19b-3p levels in Responder patients at 12-month follow-up. We then explored whether MEG3 genetic variability contributes to miRNA modulation. First, we observed that the MEG3 rs941576 genetic variant appears to influence the expression levels of hsa-miR-19a-3p and hsa-miR-19b-3p. Next, in silico analyses indicated that this variant lies within an immune-active enhancer, altering the binding affinity for the transcription factors HIF1A/ARNT2, and suggested a link between MEG3 enhancer activity and hypoxia-responsive regulation of these miRNAs. Lastly, pathway enrichment analysis highlighted that both hsa-miR-17-5p and hsa-miR-19b-3p converge on the TGF-β signalling pathway.

Conclusion: Our findings suggest the involvement of a specific MEG3-miRNA network in modulating the response to biological therapies in PsA.