Endoplasmic reticulum stress-dependent ROS production mediates synovial myofibroblastic differentiation in the immobilization-induced rat knee joint contracture model

被引:23
作者
Jiang, Shihai [1 ]
He, Ronghan [1 ]
Zhu, Lei [2 ]
Liang, Tangzhao [1 ]
Wang, Zhe [1 ]
Lu, Yunxiang [1 ]
Ren, Jianhua [1 ]
Yi, Xiaoyou [1 ]
Xiao, Dahai [1 ]
Wang, Kun [1 ]
机构
[1] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Joint & Trauma Surg, 600 Tianhe Rd, Guangzhou 510630, Guangdong, Peoples R China
[2] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Plast Surg, Guangzhou 510630, Guangdong, Peoples R China
基金
中国国家自然科学基金;
关键词
Joint contractures; Synovial myofibroblast; Endoplasmic reticulum stress; Unfolded protein response; Reactive oxygen species; UNFOLDED PROTEIN RESPONSE; ER STRESS; OXIDATIVE STRESS; TRANSFORMING GROWTH-FACTOR-BETA-1; PROLONGED IMMOBILIZATION; TRANSCRIPTION FACTOR; HUMAN-DISEASE; CELL FATE; FIBROSIS; EXPRESSION;
D O I
10.1016/j.yexcr.2018.05.036
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Joint contracture is a common complication for people with joint immobility that involves fibrosis structural alteration in the joint capsule. Considering that endoplasmic reticulum (ER) stress plays a prominent role in the promotion of tissue fibrosis, we investigated whether the unfolded protein response (UPR) contributes to the fibrotic development in immobilization-induced knee joint contractures. Using a non-traumatic rat knee joint contracture model, twelve female Sprague-Dawley rats received knee joint immobilization for a period of 8 weeks. We found that fibrosis protein markers (type I collagen, alpha-SMA) and UPR (GRP78, ATF6 alpha, XBP1s) markers were parallelly upregulated in rat primary cultured synovial myofibroblasts. In the same cell types, pretreatment with an ER stress inhibitor, 4-phenylbutyric acid (4-PBA), not only abrogated cytokine TGF beta 1 stimulation but also reduced the protein level of UPR. Additionally, high reactive oxygen species (ROS) generation was detected in synovial myofibroblasts through flow cytometry, as expected. Notably, TGF beta 1-induced UPR was significantly reduced through the inhibition of ROS with antioxidants. These data suggest that ER stress act as a pro-fibrotic stimulus through the overexpression of ROS in synovial fibroblasts. Interestingly, immunohistochemical results showed an increase in the UPR protein levels both in human acquired joint contractures capsule tissue and in animal knee joint contracture tissue. Together, our findings suggest that ER stress contributes to synovial myofibroblastic differentiation in joint capsule fibrosis and may also serve as a potential therapeutic target in joint contractures.
引用
收藏
页码:325 / 334
页数:10
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