Paclitaxel Inhibits Synoviocyte Migration and Inflammatory Mediator Production in Rheumatoid Arthritis

Xiaochen Chen; Haofeng Lin; Jinyang Chen; Lisheng Wu; Junqing Zhu; Yongnong Ye; Shixian Chen; Hongyan Du; Juan Li

doi:10.3389/fphar.2021.714566

Paclitaxel Inhibits Synoviocyte Migration and Inflammatory Mediator Production in Rheumatoid Arthritis

Front Pharmacol. 2021 Sep 9:12:714566. doi: 10.3389/fphar.2021.714566. eCollection 2021.

Authors

Xiaochen Chen^{1

2}, Haofeng Lin³, Jinyang Chen³, Lisheng Wu², Junqing Zhu¹, Yongnong Ye⁴, Shixian Chen¹, Hongyan Du³, Juan Li^{1

2}

Affiliations

¹ Department of Rheumatic and TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.
² Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
³ School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
⁴ Department of Drug and Device Center, Huaxin Orthopaedic Hospital, Shantou University, Guangzhou, China.

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.

Keywords: AKT/mTOR; CIA; MAPK; RA-FLSs; paclitaxel.