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Abstract Number: 946

Interleukin-34 Regulates Angiogenesis and Cell Proliferation In Inflammatory Arthritis, This Effect Is Potentiated By Hypoxia

Emese Balogh1, Mary Connolly1, Monika Biniecka1, Jennifer McCormick2, Douglas J. Veale3 and Ursula Fearon2, 1Rheumatology, Translation Research Group, Dublin Academic Medical Centre, St. Vincent's University Hospital, Dublin, Ireland, 2Dublin Academic Medical Centre, Translational Rheumatology Research Group, Dublin, Ireland, 3Rheumatology, St. Vincent's University Hospital, Dublin 4, Ireland

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Angiogenesis, inflammatory arthritis and interleukins (IL), Redox Balance

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Session Information

Title: Cytokines, Mediators, Cell-cell Adhesion, Cell Trafficking and Angiogenesis I

Session Type: Abstract Submissions (ACR)

Background/Purpose: Interleukin-34 (IL-34) is a cytokine implicated in macrophage differentiation, angiogenesis and osteoclastogenesis in inflammatory arthritis (IA). IA is characterized by synovial hypoxia, increased oxidative stress and altered angiogenesis.Our objectives was to investigate the role of IL-34 in the regulation of angiogenesis and hypoxia in IA. 

Methods: Patients with active IA (RA n=18; PsA n=5) were recruited and underwent knee arthroscopies with a subgroup of (n=6) pre-post TNF-inhibitoric (TNFi) therapy investigations. Synovial tissue (ST) was collected and in vivoST oxygen levels (tpO2) were measured. Synovial IL-34 expression was assessed by immunohistology (IHC) compared to control synovium. IL-34 expression was correlated to angiogenic marker (VEGF, Ang-2, Tie-2) expressions and proliferation marker expression (Ki67). Colocalisation of IL-34 with actin and vimentin was examined by dual-immunofluorescence (IF). IA fibroblast-like synoviocytes (IAFSCs, n=8) and human microvascular endothelial cells (HMVECs) were stimulated with IL-34 under normoxia and 3% hypoxia, then proliferation and tube formation assays were performed. IL-34 induced IASFC VEGF expression was measured by ELISA. Baseline mRNA levels of IASFCs were compared to osteoarthritic fibroblasts (OASFCs) by RT-PCR and followed up after TNFα stimulation. The effect of IL-34 on matrix metalloproteinase expression (MMP-2, MMP-9) was examined by zymography, IL-34 induced mononuclear cell (PBMC) adhesion to HMVECs was examined by adhesion assay.

Results: The baseline mean tpO2 level was hypoxic at 25.94 mmHg (3.3%). IL-34 expression was observed through the synovium with higher expression in the vascular (VC) regions compared to the lining (LL) and sub-lining (SL). Expression levels were higher in any layers than in the healthy synovium (p<0.05). Synovial IL-34 expression correlated with VEGF (r=0.60, p=0.011), Tie2 (r=0.50, p=0.021), Ang2 (r=0.70, p=0.013) and Ki67 (r=0.56, p=0.025) and with macroscopic vascularity (r=0.47, p=0.043). Posttherapeuthic synovial IL-34 expression significantly decreased in SL and VC layers (p=0.039, p=0.026) with a simultaneous tpO2increase from 20.9 to 23.2 mmHg. Baseline synovial IL-34 expression showed colocalisation with actin and vimentin. Basal IL-34 mRNA expression was higher in IASFCs than in OASFCs (p<0.05), the previous one was further potentiated by TNFα stimulation (p<0.05). IL-34 induced IASFC proliferation and HMVEC tube formation (all p<0.05), this effect was potentiated by 3% hypoxia (p<0.05). Furthermore IL-34 induced VEGF expression in IASFCs and stimulated PBMC adhesion to HMVECs as well as facilitated MMP-2 and MMP-9 expression in vitro.

Conclusion: IL-34 is strongly associated with synovial inflammation and promotes synovial angiogenesis and cell proliferation, an effect that is potentiated by hypoxia.


Disclosure:

E. Balogh,

AbbVie, Pfizer, MSD, Roche,

2;

M. Connolly,

AbbVie, Pfizer, MSD, Roche,

2;

M. Biniecka,

AbbVie, Pfizer, MSD, Roche,

2;

J. McCormick,

AbbVie, Pfizer, MSD, Roche,

2;

D. J. Veale,

AbbVie, Pfizer, MSD, Roche,

2,

Pfizer, Roche,

5,

Abbott, Pfizer, MSD, Roche,

8;

U. Fearon,

AbbVie, Pfizer, MSD, Roche,

2.

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