Oncotarget

Research Papers:

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

Ping Miao, Xiao Wei Zhou, Ping Wang, Rong Zhao, Ninan Chen, Chao Ying Hu, Xue Hua Chen, Liu Qian, Qi Wen Yu, Ji Ying Zhang, Rong Xu, Dong Yi He, Lian Bo Xiao, Pu Li _, Mason Lu and Dong Qing Zhang

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Oncotarget. 2018; 9:20366-20376. https://doi.org/10.18632/oncotarget.23917

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Abstract

Ping Miao1,4,*, Xiao Wei Zhou2,4,*, Ping Wang3,4,*, Rong Zhao4,5, Ninan Chen4,6, Chao Ying Hu4,7, Xue Hua Chen6, Liu Qian4, Qi Wen Yu4, Ji Ying Zhang4, Rong Xu8, Dong Yi He8, Lian Bo Xiao8, Pu Li6, Mason Lu9 and Dong Qing Zhang4

1Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

2Reproductive Medical Center of Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

3Shanghai Jiao Tong University School of Medicine, XinHua Hospital, Shanghai, China

4Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

5Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

6Department of Pediatrics, Ruijin Hospital and Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China

7Central laboratory, Shanghai Xuhui Central Hospital, Shanghai, China

8Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China

9MedAbome, Inc, Fremont, CA, USA

*These authors have contributed equally to this work

Correspondence to:

Pu Li, email: leerockygood@yahoo.com

Mason Lu, email: mmjj78@gmail.com

Dong Qing Zhang, email: dqzhang1333@163.com

Keywords: rheumatoid arthritis; gp130; collagen II antibody-induced arthritis; receptor activator of nuclear factor κB ligand; STAT3

Received: September 07, 2017    Accepted: December 11, 2017    Published: January 04, 2018

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 is hyperactive in RA and OA. M10 may be the basis for a novel RA treatment drug.


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