Abstract
Hypoxia stimulates synovial hypoperfusion in rheumatoid arthritis (RA). TXNDC5 stimulates cellular proliferation in hypoxic conditions. We previously detected increased TXNDC5 expression in synovial tissues and blood from RA patients and demonstrated that the gene encoding TXNDC5 increased RA risk. The present study investigated the pathogenic roles of TXNDC5 in RA. Transgenic mice that over-expressed TXNDC5 (TXNDC5-Tg) were generated using C57BL/6J mice and treated with bovine collagen II to induce arthritis (CIA). Synovial fibroblasts from RA patients (RASFs) were cultured and incubated with TXNDC5-siRNA or CoCl2, a chemical that induces hypoxia. CIA was observed in 80% of the TXNDC5-Tg, but only 20% of the wild-type mice (WT) developed CIA. The clinical arthritis scores reached 5 in the TXNDC5-Tg, but this index only reached 2 in the control mice. CIA TXNDC5-Tg exhibited clear pannus proliferation and bone erosion in joint tissues. A significant increase in CD4 T cells was observed in the thymus and spleen of TXNDC5-Tg during CIA. Serum levels of anti-collagen II IgG, IgG1 and IgG2a antibodies were significantly elevated in the mice. Increased cell proliferation, cell migration and TXNDC5 expression were observed in RASFs following incubation with 1 µM CoCl2. However, this effect was diminished when TXNDC5 expression was inhibited with 100 nM siRNA. TNF-alpha, IL-1α, IL-1β and IL-17 levels were significantly increased in the blood of TXNDC5-Tg mice, but the levels of these cytokines declined in the supernatant of RASFs that were treated with TXNDC5 siRNA. The expression of adiponectin, a cytokine-like mediator, decreased significantly in RASFs following TXNDC5 siRNA treatment. These results suggest that TXNDC5-over-expressing mice were susceptible to CIA. This study also suggests that hypoxia induced TXCNDC5 expression, which contributed to adiponectin expression, cytokine production and the cellular proliferation and migration of fibroblasts in RA.
Highlights
Thioredoxin domain-containing protein 5 (TXNDC5) is a protein-disulfide isomerase in the thioredoxin family
TNF-alpha, IL-1a, IL-1b and IL-17 levels were significantly increased in the blood of TXNDC5-Tg mice, but the levels of these cytokines declined in the supernatant of RASFs that were treated with TXNDC5 siRNA
The transgenic founder (F0) mice were mated with wildtype C57BL/6J mice to produce the F1 generation, and the TXNDC5 insert was detected in the F1 transgenic mice
Summary
Thioredoxin domain-containing protein 5 (TXNDC5) is a protein-disulfide isomerase in the thioredoxin family. Members of this family interact with a broad range of proteins to reversibly oxidize two cysteine thiol groups to a disulfide bridge via a redox mechanism [1]. TXNDC5 expression is up-regulated by hypoxia and protects endothelial cells from hypoxia-induced cell death [2]. We previously used proteomics to detect an increase in TXNDC5 expression in the synovial tissues of RA patients. We detected significantly elevated TXNDC5 levels in the synovial fluids and blood of RA patients [4]. We observed that 9 SNPs in the TXNDC5 encoding gene exhibit a significant association with RA risk [5]
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