Abstract
Activated fibroblast-like synoviocytes (FLSs) play a crucial role in the pathogenesis and progression of rheumatoid arthritis (RA). It is urgent to develop new drugs that can effectively inhibit the abnormal activation of RA-FLS. In our study, the RA-FLS cell line, MH7A, and mice with collagen-induced arthritis (CIA) were used to evaluate the effect of paclitaxel (PTX). Based on the results, PTX inhibited the migration of RA-FLS in a dose-dependent manner and significantly reduced the spontaneous expression of IL-6, IL-8, and RANKL mRNA and TNF-α-induced transcription of the IL-1 β, IL-8, MMP-8, and MMP-9 genes. However, PTX had no significant effect on apoptosis in RA-FLS. Mechanistic studies revealed that PTX significantly inhibited the TNF-α-induced phosphorylation of ERK1/2 and JNK in the mitogen-activated protein kinase (MAPK) pathway and suppressed the TNF-α-induced activation of AKT, p70S6K, 4EBP1, and HIF-1α in the AKT/mTOR pathway. Moreover, PTX alleviated synovitis and bone destruction in CIA mice. In conclusion, PTX inhibits the migration and inflammatory mediator production of RA-FLS by targeting the MAPK and AKT/mTOR signaling pathways, which provides an experimental basis for the potential application in the treatment of RA.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive synovitis and bone destruction
Studies have shown that PTX are able to induce apoptosis of tumor cells (Zhao et al, 2019; Xiaomeng et al, 2020); we explored whether PTX could induce rheumatoid arthritis (RA)-fibroblast-like synoviocytes (FLSs) apoptosis using Annexin-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining
We demonstrated that PTX could inhibit the migration and expression of inflammatory cytokines in RAFLS, which may be related to the inhibition of the mitogen-activated protein kinase (MAPK) and AKT/mTOR pathways
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive synovitis and bone destruction. Important advances have been made in treatment of RA in recent years, existing therapies are unable to prevent the progression of RA. The treatment of refractory synovitis in RA remains tricky (Buch et al, 2021). Fibroblast-like synoviocytes (FLSs) are a prominent component of hyperplastic synovial pannus, which mediate cartilage and bone damage in RA (Bartok and Firestein, 2010). FLSs are overactivated in RA and show abnormal biological behavior, including excessive proliferation, migration, invasion, and secretion of inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8). Increasing evidence suggests that the inhibition of the aggressive behavior of FLSs may be promising for ameliorating joint damage in RA (Masoumi et al, 2020)
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