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STAT3 Mediates the Differential Effects of Oncostatin M and TNFα on RA Synovial Fibroblast and Endothelial Cell

Megan M Hanlon1, Tatsiana Rakovich1, Clare C Cunningham1

  • 1Molecular Rheumatology, Trinity Biomedical Sciences Institute, TCD, Dublin, Ireland.

Frontiers in Immunology
|September 27, 2019
PubMed

Insights

Oncostatin M (OSM) and TNFα synergistically alter cellular energy and invasion in Rheumatoid Arthritis synovial cells. STAT3 activation in these cells drives differential effects, suggesting new therapeutic targets for TNFi-resistant patients.

Area of Science:

  • Immunology
  • Cell Biology
  • Metabolic Research

Background:

  • Autoimmune diseases like Rheumatoid Arthritis (RA) involve complex cytokine signaling.
  • Oncostatin M (OSM), a gp130/IL-6 family cytokine, is implicated in RA pathogenesis.
  • Understanding OSM's role in RA synovial cell function is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate how Oncostatin M (OSM) interacts with TNFα to regulate cellular bioenergetics and invasive functions in Rheumatoid Arthritis (RA) synovial cells.
  • To elucidate the specific mechanisms, including metabolic reprogramming and STAT3 activation, underlying these interactions.
  • To identify potential therapeutic targets for RA, especially for patients unresponsive to TNF inhibitors (TNFi).

Main Methods:

  • Primary RA synovial fibroblasts (RAFLS) and human umbilical vein endothelial cells (HUVEC) were treated with OSM alone or with TNFα.
  • Gene and protein expression (cytokines, adhesion molecules, metabolic genes, STAT3) were analyzed using real-time PCR and Western blot.
  • Cellular functions including invasion, angiogenesis, and adhesion were assessed using functional assays.
  • Cellular bioenergetics (glycolysis vs. mitochondrial respiration) were measured using Seahorse XF analysis.

Main Results:

  • OSM differentially regulated pro-inflammatory mediators and adhesion molecules in RAFLS and HUVEC.
  • OSM promoted angiogenesis, adhesion, and invasion, altering cellular bioenergetics towards glycolysis (increased ECAR/OCR ratio, GLUT-1, HK2, PFKFB3, HIF1α).
  • OSM and TNFα synergistically induced STAT3 transcriptional activity specifically in RAFLS, leading to metabolic reprogramming (glycolysis increase, mitochondrial respiration decrease), but not in HUVEC.

Conclusions:

  • STAT3 mediates the differential effects of OSM and TNFα on RAFLS and endothelial cell (EC) function.
  • Targeting OSM or its downstream signaling pathways, particularly STAT3, offers potential therapeutic or adjuvant strategies for RA.
  • These strategies may benefit patients with suboptimal responses to current TNFi therapies.
Keywords:
JAK-STAT signalingcellular bioenergeticspro-inflammatory cytokinesrheumatoid arthritissynovial fibroblasts

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