Matrine induces the apoptosis of fibroblast-like synoviocytes derived from rats with collagen-induced arthritis by suppressing the activation of the JAK/STAT signaling pathway.
Matrine induces the apoptosis of fibroblast-like synoviocytes derived from rats with collagen-induced arthritis by suppressing the activation of the JAK/STAT signaling pathway.
复制标题
苦参碱通过抑制 JAK/STAT 信号通路的激活，诱导胶原性关节炎大鼠成纤维样滑膜细胞凋亡
DOI：
10.3892/ijmm.2016.2843
复制
发表时间：
2017-02
影响因子：
5.4
通讯作者：
Li R
中科院分区：
文献类型：
--
作者：
Yang Y;Dong Q;Li R
类风湿性关节炎（RA）中的Janus激酶/信号转导子和转录激活子（JAK/STAT）信号传导与抗风湿性关节炎滑膜组织细胞的诱导有关。成纤维细胞样滑膜细胞（FLS）的过度增殖和固有的抗凋亡性是RA发生的重要机制。然而，苦参碱对RA FLS的影响尚不清楚。本研究旨在探讨苦参碱对胶原诱导性关节炎（CIA）大鼠模型的作用机制。用牛II型胶原建立CIA模型。从对照和CIA大鼠中分离FLS，体外培养，并证实具有成纤维细胞样特征。用不同浓度的苦参碱、JAK 2抑制剂AG 490或两种药物的组合处理FLS后，评估细胞增殖、凋亡率、凋亡标志物的表达和JAK/STAT通路的激活。此外，CIA大鼠通过口服管饲法给予苦参碱或甲氨蝶呤，以检查治疗干预对关节炎发病机制的影响。测量关节炎指数（AI），并对踝关节结构进行组织学分析，以确定CIA的严重程度。此外，还在体内检查了凋亡标志物和JAK/STAT家族成员的表达水平。与CIA组相比，苦参碱可降低AI，改善踝关节病理。苦参碱在体外也能抑制FLS增殖，诱导G 0/G1期细胞阻滞，并增加凋亡率。苦参碱对细胞凋亡诱导的影响进一步证实了观察，Bcl-2水平降低，而Bax和caspase-3水平增加苦参碱处理的滑膜组织和FLS。最后，苦参碱处理也减少了磷酸化，因此激活JAK 2，STAT 1和STAT 3。提示苦参碱可能通过抑制JAK/STAT信号通路的激活而诱导CIA大鼠FLS的凋亡。
The induction of apoptosis-resistant rheumatoid synovial tissue cells has been related to constitutively active Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling in rheumatoid arthritis (RA). The excessive proliferation and inherent resistance to apoptosis of fibroblast-like synoviocytes (FLS) is an important mechanism by which RA originates. However, the effects of matrine on FLS in RA is unclear. The present study aimed to investigate the mechanism of action of matrine in a rat model of collagen-induced arthritis (CIA). The CIA model was established using bovine type II collagen. FLS were isolated from control and CIA rats, cultured in vitro, and confirmed to harbor fibroblast-like characteristics. After treatment of FLS with varying concentrations of matrine, the JAK2 inhibitor AG490, or a combination of both drugs, cell proliferation, apoptosis rate, expression of apoptotic markers and the activation of the JAK/STAT pathway were assessed. Additionally, CIA rats were administered either matrine or methotrexate by oral gavage to examine the effects of therapeutic intervention on arthritis pathogenesis. The arthritis index (AI) was measured and ankle joint structure was analyzed histologically to determine the severity of CIA. Furthermore, expression levels of apoptotic markers and members of the JAK/STAT family were also examined in vivo. Compared with the CIA group, matrine reduced AI and improved ankle pathology. Matrine also inhibited FLS proliferation, induced G0/G1 cell cycle arrest, and increased the rate of apoptosis in vitro. The effects of matrine on apoptosis induction were further confirmed by observations that Bcl-2 levels were decreased, whereas Bax and caspase-3 levels were increased in the matrine-treated synovial tissues and FLS. Finally, matrine treatment also diminished the phosphorylation, and hence activation of JAK2, STAT1 and STAT3. Our results suggest that matrine induces the apop-tosis of FLS from rats with CIA by inhibiting activation of the JAK/STAT signaling pathway.