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

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.

TDZD-8 Suppresses Rheumatoid Arthritis Induced by Collagen Type II in Rats: Potential Role of Apoptosis and Inflammation

“…To determine whether the treatment protocol by TDZD-8 used here can inhibit RF, which is a well-known RA marker (Gavrila et al, 2016;Lu et al, 2018), we assessed, in the four groups of rats, the RF blood levels. As shown in Figure 3B, immunization of rats with COII substantially (p<0.05) augmented RF levels in the model group (COII) that were substantially (p<0.05) but incompletely suppressed by COII+TDZD-8since the levels of RF in the treated group (COII+TDZD-8) were higher compared with control rats.…”

Thioredoxin Modulates Protein Arginine Deiminase 4 (PAD4)-Catalyzed Citrullination

“…By contrast, oxidative stress induces hTRX production during infection and inflammation, and acts as a chemoattractant for immune cells such as neutrophils, monocytes and T-cells (59, 60). Consequently, hTRX levels are elevated in serum, synovial fluid, and synovial tissues of RA patients (38–42). Here, we provide a potential link between high TRX levels and enhanced protein citrullination during RA.…”

“…Since redox balance is a necessary requirement for PAD activity, thioredoxin (hTRX), a 12 kDa protein that regulates redox homoeostasis in all tissues of the human body (35–37), is another candidate that could impact PAD-catalyzed citrullination. In fact, numerous studies have shown elevated levels of hTRX in serum and synovial samples from RA patients (38–42) suggesting hTRX activity might contribute to RA progression; however its role in PAD activation has yet been established.…”

The impact of thioredoxin reduction of allosteric disulfide bonds on the therapeutic potential of monoclonal antibodies

“…Furthermore, FLS cells can migrate to, and cause pathology in, other joints. Thus, Trx contributes to disease progression (20).…”