Suppressive Effects of TSAHC in an Experimental Mouse Model and Fibroblast-Like Synoviocytes of Rheumatoid Arthritis

Abstract

The purpose of this study is to investigate the effect of TSAHC [4'-(p-toluenesulfonylamido)-4-hydroxychalcone] in K/BxN serum transfer arthritis model and fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLS). In in vivo experiments, TSAHC attenuated the incidence and severity of arthritis in comparison with the vehicle group. Histological findings showed that TSAHC decreased the inflammation, bone erosion, cartilage damage, and osteoclasts activity in the ankle. Furthermore, we confirmed by biochemical analysis that the observations were associated with the decreased expression of proinflammatory cytokines, matrix metalloproteinases (MMPs), and RANKL in serum and ankle. In in vitro experiments, TSAHC induced apoptosis, while it significantly suppressed tumor necrosis factor-α (TNF-α)-induced cell proliferation in RA-FLS. Moreover, TSAHC inhibited mRNA expression of TNF-α-induced interleukin (IL)-6, MMP-1, MMP-3, and MMP-13. Evaluation of signaling events showed that TSAHC inhibited the translocation and transcriptional activity of nuclear factor-kappa B (NF-κB) by regulating phosphorylated-IκB-α (p-IκB-α) and IκB-α in TNF-α-induced RA-FLS. Our results suggest that TSAHC inhibits experimental arthritis in mice and suppresses TNF-α-induced RA-FLS activities via NF-κB pathway. Therefore, TSAHC may have therapeutic potential for the treatment of RA.

Knockdown of YAP/TAZ Inhibits the Migration and Invasion of Fibroblast Synovial Cells in Rheumatoid Arthritis by Regulating Autophagy

“…Our former work demonstrated that both TAZ knockdown and knockout inhibited the migration, invasion, and EMT and promoted autophagy of the hepatocellular carcinoma cell lines [ 25 ]. Since RA-FLS present tumor-like characteristics of excessive migration and invasion towards cartilage and bone and play an important role in cartilage degradation and bone destruction [ 2 – 7 ], targeting the invasive property of RA-FLS is more important for RA therapy. Here, we report that RA-FLS display overexpression of YAP and TAZ.…”

“…In the current study, we clearly demonstrated that YAP and TAZ in RA-FLS exhibited higher expression than those in normal FLS, which was consistent with the results in multiple human cancer cells, implying that YAP and TAZ might serve function as the regulators in RA-FLS. Since RA-FLS can migrate and invade the articular cartilage and bone, thereby leading to destruction of cartilage and bone [ 6 , 7 ], we firstly established RA-FLS stable knockdown of YAP or TAZ using the lentiviral-mediated YAP or TAZ knockdown approaches to evaluate the effect of YAP or TAZ knockdown on migration and invasion of RA-FLS by wound healing and Transwell migration and invasion assays. Our data demonstrated that either knockdown of YAP or TAZ markedly decreased cell motility, indicating the role of loss of YAP or TAZ resulting in the inhibition of the aggressive invasive ability of RA-FLS.…”

“…Evidence is accumulating that the fibroblast-like synoviocytes from RA patients (RA-FLS) play a pivotal role in the pathogenesis of RA [ 1 ]. RA-FLS exhibit some tumor cell-like characteristics, such as excessive proliferation, migration, and invasion; anchorage-independent proliferation; and lack of contact inhibition in vitro [ 2 – 4 ], and can migrate and invade the articular cartilage and bone [ 5 ], contributing to the destruction of cartilage and bone and joint damage through secretion of proinflammation cytokines and production of the proteolytic enzymes such as matrix metalloproteinases (MMPs) [ 6 , 7 ]. Therefore, understanding and investigating the factors that regulate the migration and invasion of RA-FLS might provide novel targets for RA therapy.…”

Blocking translationally controlled tumor protein attenuate aggressiveness of fibroblast-like synoviocytes and ameliorates collagen-induced arthritis

“…Wound closure and cell invasion assays were performed as described previously (Jeon et al, 2017). In brief, RA-FLS monolayers, grown to confluence on 60-mm culture dishes, were scratched with a sterile 200-μl pipette tip and then treated with 75 nM dH/T2, or 75 nM dH/T plus 75 nM dTBP2.…”

“…Synovial inflammation, cartilage damage, and bone erosion were evaluated and TRAP-positive multinucleated osteoclasts (with [?] 3 nuclei) were counted as described previously (Jeon et al, 2017).…”