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Altered expression of microRNA-23a in psoriatic arthritis modulates synovial fibroblast pro-inflammatory mechanisms

Sarah M Wade1, Michelle Trenkmann2, Trudy McGarry1

  • 1Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital, University College Dublin, Dublin, Ireland.

Journal of Autoimmunity
|September 6, 2018
PubMed
Abstract

Insights

In psoriatic arthritis (PsA), lower miR-23a expression promotes synovial fibroblast activation and inflammation. Blocking PDE4 signaling offers a novel therapeutic approach for PsA by inhibiting this pathway.

Area of Science:

  • Immunology
  • Molecular Biology
  • Rheumatology

Background:

  • Psoriatic arthritis (PsA) involves synovial inflammation driven by fibroblast activation.
  • MicroRNAs (miRNAs) play crucial roles in regulating cellular processes, including inflammation.
  • The specific role of miR-23a in PsA synovial fibroblast (SFC) activation remains unclear.

Purpose of the Study:

  • To investigate the functional role of miR-23a in synovial fibroblast activation in psoriatic arthritis (PsA).
  • To elucidate the molecular mechanisms underlying miR-23a's regulation of SFCs in PsA.
  • To explore the potential of targeting miR-23a or its downstream pathways for PsA therapy.

Main Methods:

  • Real-time quantitative PCR (RT-qPCR) was used to assess miR-23a cluster expression in PsA and osteoarthritis (OA) tissues and peripheral blood mononuclear cells (PBMCs).
  • PsA SFCs were stimulated with Toll-like receptor (TLR) ligands and cytokines, and transfected with miR-23a inhibitors to evaluate effects on migration, invasion, and inflammatory mediator secretion.
  • Luciferase reporter assays, RT-PCR, and Western blotting were employed to confirm the direct interaction between miR-23a and its target, phosphodiesterase 4B (PDE4B).
  • The functional role of PDE4B signaling was assessed using a PDE4 inhibitor in miR-23a and Poly(I:C)-induced PsA SFC activation models.

Main Results:

  • miR-23a expression was significantly lower in PsA synovial tissue compared to OA and inversely correlated with disease activity and synovitis.
  • TLR activation (Poly(I:C), LPS) decreased miR-23a expression in PsA SFCs, leading to enhanced migration, invasion, and secretion of pro-inflammatory cytokines (IL-6, IL-8, MCP-1, RANTES, VEGF).
  • PDE4B was identified as a direct target of miR-23a, with its expression upregulated upon miR-23a inhibition. Blockade of PDE4 signaling attenuated miR-23a and Poly(I:C)-induced SFC activation.

Conclusions:

  • Dysregulated miR-23a expression in PsA contributes to synovial inflammation by enhancing SFC activation via PDE4B signaling.
  • PDE4B signaling represents a key mediator in miR-23a-driven PsA pathogenesis.
  • Targeting PDE4 signaling offers a novel therapeutic strategy for managing psoriatic arthritis by mitigating synovial inflammation.

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