Regulatory effect of anti-gp130 functional mAb on IL-6 mediated RANKL and Wnt5a expression through JAK-STAT3 signaling pathway in FLS

Oncotarget
Ping MiaoDong Qing Zhang

Abstract

We investigated the effect on rheumatoid arthritis (RA) of an anti-gp130 monoclonal antibody (mAb) and its mechanism using RA fibroblast-like synoviocytes (FLS) and a collagen antibody-induced arthritis (CAIA) mouse model. We determined the interleukin 6 (IL-6), IL-6 receptor α (IL-6Rα), gp130, receptor activator of nuclear factor κB ligand (RANKL), matrix metalloproteinase 3 (MMP3), TIMP metallopeptidase inhibitor 1 (TIMP1), and Bcl-2 levels in RA and osteoarthritis (OA) serum and synovial fluid. RA FLS were cultured with or without IL-6/IL-6Rα; WNT5A and RANKL levels were detected. We generated an anti-gp130 mAb (M10) with higher affinity and specificity, blocked IL-6 signaling with it, and assessed its effects on the CAIA model, WNT5A and RANKL expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation. The IL-6 signaling system in patients with RA was increased; RANKL, MMP3, TIMP1, and Bcl-2 in RA bone were elevated. IL-6/IL-6Rα increased RA FLS WNT5A and RANKL expression. M10 ameliorated arthritis in the CAIA model, and inhibited RANKL, WNT5A, and Bcl-2 expression in RA FLS by blocking IL-6 signaling, likely via Janus kinase-STAT3 pathway downregulation. The IL-6-soluble IL-6Rα-gp130 complex...Continue Reading

References

May 26, 2007·Nature Reviews. Immunology·Iain B McInnes, Georg Schett
Feb 24, 2010·Nature Reviews. Rheumatology·Cem GabayGaby Palmer
Dec 14, 2011·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Martina RaunerLorenz C Hofbauer
Oct 17, 2012·Nature Reviews. Rheumatology·Hiroshi Takayanagi
Jun 5, 2013·Joint, Bone, Spine : Revue Du Rhumatisme·Benoit Le GoffDominique Heymann
Apr 4, 2015·International Immunopharmacology·Daniela RossiDario Roccatello

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Citations

Nov 9, 2019·International Journal of Molecular Sciences·Kazuhiro MaedaKeishi Marumo

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Datasets Mentioned

BETA
GM-CSF

Methods Mentioned

BETA
ELISA
antibody affinity purification
flow cytometry
FACS
PCR
affinity purification
protein assay
electrophoresis

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