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Abstract Number: 2800

Tofacitinib Regulates Synovial Angiogenesis in Psoriatic Arthritis through Induction of Negative Feedback Inhibitors

Wei Gao, Jennifer McCormick, Carl Orr, Mary Connolly, Ursula Fearon and Douglas J. Veale, Dublin Academic Medical Centre, Translational Rheumatology Research Group, Dublin, Ireland

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Angiogenesis, cytokines and rheumatoid arthritis (RA)

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Session Information

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

Session Type: Abstract Submissions (ACR)

Background/Purpose: Psoriatic Arthritis (PsA) is a common, chronic immune-mediated inflammatory disease, characterised by synovitis, progressive destruction of articular cartilage/bone, and is associated with psoriasis. Janus Kinase and Signal Transducer and Activator of Transcription (JAK/STAT), a critical signalling pathway involved in inflammatory mechanisms, has been implicated in the pathogenesis of PsA. This study was to examine the mechanistic effect of Tofacitinib (A novel JAK inhibitor CP-690,550) on pro-inflammatory pathways using ex vivo and  in vivo models of PsA.

Methods: PsA whole tissue synovial explant cultures were established from PsA biopsies obtained under direct visualisation at arthroscopy. This explant model maintains the architecture and cell-cell contact of the synovial tissue,  spontaneously releases pro-inflammatory mediators and therefore closely reflects the in vivo inflamed microenvironment. Primary PsA synovial fibroblasts (PsASFC) were also isolated from PsA synovial biopsies.  Phospho-STAT3 (p-STAT3), phospho-STAT1 (p-STAT1), Suppressor of Cytokine Signaling 3 (SOCS3) and Protein Inhibitor of Activated Stat 3 (PIAS3) expression were quantified by Western Blot in PsA synovial explants and PsASFC following culture with Tofacitinib (1μM) or vehicle control. Cytokine expression of IL-6, IL-8 and IL-10 in ex vivo culture synovial explants in response to Tofacitinib (0.5μM-1μM) were assessed by ELISA. Furthermore the effect of Tofacitinib (0.5μM-1μM) on PsASFC migration, invasion, matrigel network formation and MMP2/9 were quantified by wound repair assays, transwell invasion chambers and zymography.

 Results: Tofacitinib significantly decreased p-STAT3 and p-STAT1 expression in PsA synovial tissue explant cultures ex vivo and in primary PsASFC (p<0.05). In contrast Tofacitinib induced SOCS3 and PIAS3 expression in both models (p<0.05). In parallel Tofacitinib significantly decreased spontaneous secretion of IL-6 (p<0.05), IL-8 (p<0.05) and induced IL-10 (p<0.05) expression in PsA explant cultures.  Functionally, PsASFC invasion, matrigel network/tube formation, migration, and pro-MMP-2/-9 activities, were inhibited in the presence of Tofacitinib (p<0.05). 

Conclusion: This is the first study to demonstrate Jak/STAT signaling and the effect of Tofacitinib on these pathways in PsA synovial tissue and  primary PsA synovial fibroblasts. Tofacitinib mediated specific JAK-STAT signaling components, inhibited key pro-inflammatory cytokines and invasion/migrational mechanisms. Thus this data further supports the use of JAK-STAT inhibition as a potential therapeutic agent for the treatment of PsA.


Disclosure:

W. Gao,
None;

J. McCormick,
None;

C. Orr,
None;

M. Connolly,
None;

U. Fearon,
None;

D. J. Veale,

Abbvie,

2,

MSD,

2,

Pfizer Inc,

2,

Roche ,

2,

Pfizer ,

5,

Roche ,

5,

Abbott,

8,

MSD,

8,

Pfizer,

8,

Roche ,

8.

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