Therapeutic effects of matrine derivate MASM in mice with collagen-induced arthritis and on fibroblast-like synoviocytes

Yuming Zou,Chao Li,Qing Cai,Jia Li,Denghui Liu,Weidong Xu,Qingjie Zhao,Quan Li

doi:10.1038/s41598-017-02423-7

Abstract

MASM is a matrine derivate that exhibits a number of pharmacological effects, including immunosuppressive activity and anti-inflammatory properties. In this study, the mechanisms underlying the therapeutic efficacy of MASM in the treatment of rheumatoid arthritis were investigated using DBA/1 mice with collagen-induced arthritis (CIA) and fibroblast-like synoviocytes derived from rheumatoid arthritis patients (RA-FLS). We demonstrated that MASM markedly attenuated the severity of arthritis in CIA mice. The therapeutic effects were associated with ameliorated joint swelling and reduced bone erosion and destruction. Furthermore, the administration of MASM suppressed the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). In vitro, MASM inhibited the expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-8) and matrix metalloproteinases (MMP-1, MMP-3 and MMP-13) by inhibiting both the phosphorylation of MAPKs and the activation of NF-κB in IL-1β-stimulated RA-FLS. Additionally, MASM could induce apoptosis of RA-FLS via mitochondrial and Akt signaling pathways in human RA-FLS. These findings suggest that MASM could attenuate arthritis severity in CIA mice at least partially by blocking the phosphorylation of MAPKs and the activation of NF-κB and by inducing apoptosis in RA-FLS. MASM could be a potent therapeutic agent for the treatment of RA.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease and is characterized by leukocyte infiltration and synovial hyperplasia that causes chronic joint inflammation as well as the subsequent erosion of cartilage and bone[1, 2]
Hind paw thickness was measured to analyze the beneficial effects of MASM, and the results were correlated with clinical scores (Fig. 1C)
We demonstrated that MASM effectively suppressed inflammatory responses and joint destruction in collagen-induced arthritis (CIA) mice

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease and is characterized by leukocyte infiltration and synovial hyperplasia that causes chronic joint inflammation as well as the subsequent erosion of cartilage and bone[1, 2]. Fibroblast-like synoviocytes (RA-FLS) play a key role in RA by producing inflammatory mediators that initiate and perpetuate inflammation as well as proteases that contribute to cartilage and bone destruction. The interaction between RA-FLS and cells of the immune system or resident joint cells could lead to the promotion of ongoing inflammation and tissue destruction[3, 4]. RA-FLS are relatively resistant to apoptosis and develop a unique aggressive phenotype by forming hyperplastic synovial pannus tissue[3, 5]. Further investigation revealed that MASM could significantly suppress inflammatory responses by inhibiting both the phosphorylation of MAPKs and the activation of NF-κB. MASM induces apoptosis in human RA-FLS by activating the mitochondrial apoptosis pathway and inhibiting the Akt signaling pathway

Methods

Results

Conclusion