Tanshinone IIA promotes the apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis by up-regulating lncRNA GAS5.

Guoqing Li,Zhongbin Xia,Dan Liu,Xia Wu,Chunwang Zhang,Ying Liu,Fanru Meng,Yuxuan Fang

doi:10.1042/bsr20180626

Abstract

Rheumatoid arthritis (RA) is a common chronic autoimmune joint disease characteristic of elevated proliferation and infiltration of fibroblast-like synoviocytes (FLS). Here, we aimed to explore the mechanisms of the Tanshinone IIA (Tan IIA)-induced apoptosis of FLS from patients with RA (termed RAFLS). Cell Counting Kit-8 (CCK-8) assay and Annexin V staining revealed that RAFLS viability decreased and apoptosis increased after Tan IIA treatment. Long non-coding RNA (lncRNA) GAS5 expression was significantly decreased in the synovial tissues and RAFLS, while Tan IIA treatment resulted in an up-regulation of GAS5. Consistently, knockdown of GAS5 using siRNA inhibited RAFLS apoptosis. Mechanistically, GAS5 knockdown down-regulated the expression of cleaved caspase-3 and caspase-9 in the RAFLS cells and activated the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. These data indicate that Tan IIA promotes RAFLS apoptosis by up-regulating lncRNA GAS5, with enhanced expression of cleaved caspase-3/caspase-9 and inhibited PI3K/AKT signaling.

Highlights

Rheumatoid arthritis (RA) is a chronic autoimmune joint disease characterized by proliferation and infiltration of fibroblast-like synoviocytes (FLS), which leads to synovial hyperplasia and progressive joint destruction [1]
We investigated the involvement of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling in the anti-RA effects of Tan-Tanshinone IIA (IIA) as PI3K/AKT signaling is critical for the regulation of cell apoptosis
Our results demonstrated that the viability of RAFLS was reduced by Tan-IIA treatment in a dose- and time-dependent manner (Figure 1A–C)

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune joint disease characterized by proliferation and infiltration of fibroblast-like synoviocytes (FLS), which leads to synovial hyperplasia and progressive joint destruction [1]. In RA, activation of FLS (termed RAFLS) and their reduced apoptosis are crucial in both the initiation and progression of arthritis [2]. Tanshinone IIA (Tan IIA; 14,16-epoxy-20-nor-5(10),6,8,13,15-abietapentaene-11,12-dione) is a phytochemical derived from the roots of Salvia miltiorrhiza Bunge and is commonly used for treating a number of chronic diseases [3]. The therapeutic effects of Tan-IIA include anti-tumor, pro-apoptotic, and anti-inflammatory activities [4,5]. This prompted the use of Tan-IIA to attenuate proliferation of RAFLS, impeding the progression of RA [6]

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