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Open Access Highly Accessed Research article

Inhibition of synovitis and joint destruction by a new single domain antibody specific for cyclophilin A in two different mouse models of rheumatoid arthritis

Li Wang1, Junfeng Jia2, Conghua Wang2, Xiaokui Ma3, Chenggong Liao1, Zhiguang Fu1, Bin Wang1, Xiangmin Yang1, Ping Zhu2*, Yu Li1* and Zhinan Chen1*

Author Affiliations

1 Cell Engineering Research Centre, Cancer Biology of State Key Laboratory, Fourth Military Medical University, No. 17 West Changle Road, Xi’an 710032, Shaanxi, PR China

2 Department of Clinical Immunology, First Affiliated Hospital, Fourth Military Medical University, No. 15 West Changle Road, Xi’an 710032, Shaanxi, PR China

3 Department of Life Science, Shaanxi Normal University, Xi’an 710062, Shaanxi, PR China

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Arthritis Research & Therapy 2013, 15:R208  doi:10.1186/ar4401

Published: 5 December 2013

Abstract

Introduction

Cyclophilin A (CypA) is implicated in rheumatoid arthritis (RA) pathogenesis. We studied whether a novel anti-CypA single domain antibody (sdAb) treatment would modulate the severity of the disease in two different animal models of RA.

Methods

A novel sdAb, named sdAbA1, was screened from an immunized camel sdAb library and found to have a high binding affinity (KD = 6.9 × 10-9 M) for CypA. The SCID-HuRAg model and the collagen-induced arthritis (CIA) in mice were used to evaluate the effects of sdAbA1 treatment on inflammation and joint destruction. For in vitro analysis, monocytes/macrophages were purified from synovial fluid and peripheral blood of patients with RA and were tested for the effect of anti-CypA sdAb on metalloproteinase (MMP) production. Human monocyte cell line THP-1 cells were selected and western blot analyses were performed to examine the potential signaling pathways.

Results

In the CIA model of RA, the sdAbA1 treatment resulted in a significant decrease in clinical symptoms as well as of joint damage (P <0.05). In the SCID-HuRAg model, treatment with anti-CypA antibody sdAbA1 significantly reduced cartilage erosion, inflammatory cell numbers and MMP-9 production in the implanted tissues (P <0.05). It also significantly reduced the levels of human inflammatory cytokines IL-6 and IL-8 in mouse serum (P <0.05). No toxic effects were observed in the two animal models. In vitro results showed that sdAbA1 could counteract CypA-dependent MMP-9 secretion and IL-8 production by interfering with the ERK-NF-κB pathway.

Conclusions

Blockade of CypA significantly inhibited synovitis and cartilage/bone erosion in the two tested animal models of RA. Our findings provide evidence that sdAbA1 may be a potential therapeutic agent for RA.