Background Angiopoietin (Ang)-1 and Ang-2, and their shared receptor Tie2, are expressed in rheumatoid arthritis (RA) synovial tissue, but the cellular targets of Ang signalling and the relative contributions of Ang-1 and Ang-2 to arthritis are poorly understood.
Objectives To determine the cellular targets of Ang signalling in RA synovial tissue, and the effects of Ang-2 neutralisation in murine collagen-induced arthritis (CIA).
Methods RA and psoriatic arthritis (PsA) synovial biopsies were examined for expression of Tie2 and activated phospho (p)-Tie2 by quantitative immunohistochemistry and immunofluorescent double staining. Human monocyte and macrophage Tie2 expression was determined by flow cytometry and quantitative PCR. Regulation of macrophage intracellular signalling pathways and gene expression were examined by immunoblotting and ELISA. CIA was assessed in mice treated with saline, control antibody, prednisolone or neutralising anti-Ang-2 antibody.
Results Expression of synovial Tie2 and p-Tie2 was similar in RA and PsA. Tie2 activation in RA patient synovial tissue was predominantly localised in synovial macrophages and was expressed by human macrophage. Ang-1 and Ang-2 stimulated activation of multiple intracellular signalling pathways, and cooperated with tumour necrosis factor to induce macrophage interleukin 6 and macrophage inflammatory protein 1α production. Ang-2 selectively suppressed macrophage thrombospondin-2 production. Ang-2 neutralisation significantly decreased disease severity, synovial inflammation, neo-vascularisation and joint destruction in established CIA.
Conclusions The authors identify synovial macrophages as primary targets of Ang signalling in RA, and demonstrate that Ang-2 promotes the pro-inflammatory activation of human macrophages. Ang-2 makes requisite contributions to pathology in CIA, indicating that targeting Ang-2 may be of therapeutic benefit in the treatment of RA.
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SK and SG contributed equally to this manuscript.
Funding This research was supported in part by the Dutch Arthritis Association Project Grants (NR 04-1-301 and NR 09-1-405) to KA Reedquist. S García is supported by the Anxeles Alvariño postdoctoral programme ((I+D+I Xunta de Galicia and the European Social Fund (ESF). DL Baeten is supported by a Vidi grant from the Dutch Scientific Organization.
Competing interests MF is an employee of AstraZeneca. BN, WI, JRC, MAS and AJC are employees of MedImmune Ltd., a wholly owned subsidiary of AstraZeneca. Each of the aforementioned authors has share options in AstraZeneca greater than $10 000, and have their research funded by AstraZeneca. PPT has served as a consultant to AstraZeneca (less than $10 000 per annum) and has received research funding from MedImmune/AstraZeneca.
Ethics approval This study is approved by the Medical Ethics Committee, Academic Medical Center, University of Amsterdam.
Provenance and peer review Not commissioned; externally peer reviewed.
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