T-614 attenuates knee osteoarthritis via regulating Wnt/β-catenin signaling pathway

Abstract

Background The aim of this study was to investigate the effect of Iguratimod (T-614) on rat knee osteoarthritis (KOA) and further to explore its underlying mechanism. Methods In this study, papain-induced KOA model was constructed. Hematoxylin and eosin (H&E) staining was conducted to observe the pathological changes of cartilage tissue and Mankin scoring principle was used for quantitative scoring. Transmission electron microscopy (TEM) was applied to observe the ultrastructure of cartilage tissue. ELISA was used to measure the levels of matrix metalloproteinase 13 (MMP-13) and inflammatory factors (interleukin (IL)-6 and tumor necrosis factor a (TNF-a)) in serum. RT-qPCR and immunohistochemistry were conducted to detect mRNA expression and protein expression of key genes in Wnt/β-catenin pathway. Results H&E, Mankin scoring, and TEM data confirmed that compared with model group, T-614 significantly improved the degeneration of articular cartilage. Besides, we observed that low, middle, and high doses of T-614 could decrease the levels of MMP13, TNF-α, and IL-6 in serum to different degrees. Mechanically, T-614 downregulated the mRNA and protein expression of β-catenin and MMP13 in cartilage tissue via a dose-dependent manner, and on the contrary upregulated the mRNA and protein expression of glucogen synthase kinase-3 beta (GSK-3β). Conclusion Our results suggested that T-614 can reduce the level of its downstream target gene MMP-13 and downregulate the expression of inflammatory cytokines TNF-α and IL-6 by regulating the Wnt/β-catenin signaling pathway, thereby inhibiting joint inflammation and controlling KOA degeneration of articular cartilage.

Therapeutic Effect of Anwulignan on Knee Osteoarthritis and Its Mechanism through Cell Pyroptosis Pathway in Rats

“…In addition, AN could improve a series of biochemical indicators related to KOA in papain-induced rat KOA model. AN could decrease the levels of ROS, MDA, TNF-α, IL-6, IL-1β, IL-18, NO and PGE2, but increase the activity of SOD in the knee joint cartilage tissue to alleviate the papain-induced knee osteoarthritis in rats 32 , which are consistent with the results of previous study on the papain-induced knee osteoarthritis in rats 33 , and there were almost differences among the treatment groups in each experiment and the effects in AN-H group were most signi cant, indicating that the effects of AN were dose-dependent.…”

Chonggu Granules Improve Cartilage Matrix Metabolism in Knee Osteoarthritis via the miR-148a-3p/Wnt/β-Catenin Pathway

“…The intervention of CGG resulted in varying degrees of increased levels of COL2a1 and Aggrescan proteins in each group of rats compared to the model group, as well as decreased levels of MMP-3, MMP-13, and pro-inflammatory factors. Consistently, Cong et al 24 found that T-614 slowed KOA progression by reducing serum levels of IL-6 and TNF-α and inhibiting the secretion of serum MMP-13, thereby controlling the degradation of articular cartilage matrix. Briefly, CGG promote the synthesis of Col2 and Aggrescan, reduce the production MMPs, suppress the release of pro-inflammatory factors, thereby balancing the ECM and alleviating cartilage damage.…”

TPX2 upregulates MMP13 to promote the progression of lipopolysaccharide-induced osteoarthritis

“… Lietman et al (2018) also confirmed that blocking of WNT/β-catenin signaling could improve the severity of OA in mice through mouse experiments. Cong et al (2021) showed that T-614 could inhibit joint inflammation by the WNT/β-catenin signaling pathway and inflammatory cytokines. However, the connections between these pathways and OA warrant further exploration and verification.…”