Targeted inhibition of TXNRD1 prevents cartilage extracellular matrix degeneration by activating Nrf2 pathway in osteoarthritis

• Published in: Biochemical and biophysical research communications 2022-12, Vol.635, p.267-276
• Main Authors: Liang, Jianhui, Wang, Song, Hu, Jiawei, Hong, Xin, Zhu, Meisong, Liu, Xuqiang, Alswadeh, Momen, Mo, Fengbo, Dai, Min
• Format: Article
• Language: English
• Subjects: Animals; Auranofin; Auranofin - pharmacology; Cartilage, Articular - metabolism; Chondrocytes - metabolism; Extracellular matrix; Extracellular Matrix - metabolism; Interleukin-1beta - metabolism; Mice; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2 pathway; Osteoarthritis; Osteoarthritis - metabolism; Thioredoxin Reductase 1 - genetics; TXNRD1
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.10.059

Osteoarthritis, a prevalent orthopedic disease, can affect the elderly and causes impairment. The degradation and aberrant homeostasis of cartilage extracellular matrix figure pivotally in the progression of osteoarthritis. Thioredoxin systems plays a role in a wide range of biological processes, including cell proliferation, apoptosis, and oxidative stress. The present study aimed to investigate the unique function and underlying pathophysiological mechanism of TXNRD1 in chondrocytes. An upregulated expression of TXNRD1 was observed in the articular cartilage of osteoarthritis patients compared with normal articular cartilage. Furthermore, in vitro experiments showed that the expression of TXNRD1 was also abnormally increased in IL-1β-induced primary mouse chondrocytes. Silencing TXNRD1 using siRNA in chondrocytes could effectively inhibit the expression of ADAMTS5 and MMP13, and enhance the expression of COL2A1 and SOX9. The same was true for auranofin, an inhibitor of TXNRD1. This phenomenon indicated that inhibition of TXNRD1 attenuated il-1β-induced metabolic imbalance of extracellular matrix (ECM) and the progression of chondrocyte osteoarthritis. Further mechanism analysis revealed that the activation of Nrf2 signaling pathway and the expression of heme oxygenase-1 (HO-1) were increased upon TXNRD1 inhibition. Furthermore, auranofin was found to attenuate DMM-induced osteoarthritis progression in vivo. Therefore, the pharmacological downregulation of TXNRD1 may provide an effective novel therapy for OA. •Homeostasis of cartilage extracellular matrix plays an important role in the progression of OA.•TXNRD1 expression is upregulated in human OA cartilage and IL-1β-induced mouse Chondrocytes.•Inhibition of TXNRD1 suppresses the degeneration of ECM and regulates the expression of Nrf2 and HO-1.•Inhibition of TXNRD1 inhibits OA progression by activating Nrf2 signaling both in vivo and in vitro.