Thioredoxin 1 is associated with the proliferation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes

Tianbao Lu,Ying Lu,Shasha Fan,Shanhan Yu,Lieying Fan,Ming Zong

doi:10.1007/s10067-017-3832-1

Tianbao Lu, Ying Lu + Show 4 more

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https://doi.org/10.1007/s10067-017-3832-1

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Journal: Clinical Rheumatology	Publication Date: Sep 15, 2017
Citations: 16	License type: open-access

Affiliation: Shanghai East Hospital

Abstract

We aimed to investigate the possible effects of thioredoxin 1 (Trx1) on the proliferation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and elucidate the possible mechanisms involved. We investigated the distribution and expression of Trx1 in synovial tissues from RA and osteoarthritis (OA) patients by immunohistochemistry and real-time polymerase chain reaction (RT-PCR) analyses. RA-FLSs were isolated and cultured under normoxic (21% oxygen) or hypoxic (3% oxygen) concentrations. Transfection of Trx1-siRNAs and a Trx1 overexpression construct was conducted to manipulate the expression of Trx1. Protein expression was detected by Western blot. Doxorubicin (Adriamycin, ADR) was used to induce apoptosis. LY-294002 was used for the inhibition of PI3K-Akt. Cell proliferation and apoptosis were determined by MTS (3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt) assay and flow cytometry, respectively. The mRNA and protein expression of Trx1 in RA tissues was higher than that in OA tissues. The expression levels of Trx1 and cell proliferation in RA-FLSs were increased under hypoxia in comparison to those under normoxia. In hypoxia, downregulation of Trx1 significantly suppressed FLS proliferation, and the expression of PI3Kp85, phospho-Akt, and Bcl-2, while notably increased FLS apoptosis and the expression of active Caspase3 and Bax. In normoxia, Trx1 overexpression promoted the FLS proliferation and the expression of PI3Kp85, phospho-Akt, and Bcl-2, but inhibited FLS apoptosis and the expression of active Caspase3 and Bax in FLSs. Such effects were partially repressed by LY-294002 treatment. Trx1 may play an important role in regulating the proliferation and apoptosis of RA-FLSs by modulating PI3K-Akt activation.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory disorder and characterized by chronic joint inflammation and synovial hyperplasia, which leads to progressive destruction of articular cartilage and bone
Our previous study has found that hypoxic exposure promotes the proliferation and reduces the apoptosis of RA fibroblast-like synoviocytes (RA-FLSs) [28]
Little is known about the effect of thioredoxin 1 (Trx1) on the biological behavior of RA-FLSs

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disorder and characterized by chronic joint inflammation and synovial hyperplasia, which leads to progressive destruction of articular cartilage and bone. The synovial hyperplasia is featured by an overabundance of RA fibroblast-like synoviocytes (RA-FLSs). RA-FLSs display tumor-like destructive and invasive features and affect the inflammatory microenvironment through secreting a variety of proinflammatory factors or interacting with immune cells [1, 2]. Due to the enhanced proliferation of RA-FLSs, the oxygen consumption in RA synovium increases, which leads to synovial hypoxia and hypoperfusion [4]. In the 1970s, LundOlesen K et al first revealed the hypoxic nature of RA synovium by measuring the oxygen tension in the synovial fluid of RA patients with a Clark-type electrode [5]

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