Wu Qian, Zhong Zhao-Ming, Zhu Si-Yuan, Liao Cong-Rui, Pan Ying, Zeng Ji-Huan, Zheng Shuai, Ding Ruo-Ting, Lin Qing-Song, Ye Qing, Ye Wen-Bin, Li Wei, Chen Jian-Ting
Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
Department of Oncology, Affiliated Jiujiang Hospital of Nanchang University, Jiujiang, China.
Apoptosis. 2016 Jan;21(1):36-50. doi: 10.1007/s10495-015-1191-4.
Pro-inflammatory cytokine-induced chondrocyte apoptosis is a primary cause of cartilage destruction in the progression of rheumatoid arthritis (RA). Advanced oxidation protein products (AOPPs), a novel pro-inflammatory mediator, have been confirmed to accumulate in patients with RA. However, the effect of AOPPs accumulation on chondrocyte apoptosis and the associated cellular mechanisms remains unclear. The present study demonstrated that the plasma formation of AOPPs was enhanced in RA rats compared with normal. Then, chondrocyte were treated with AOPPs-modified rat serum albumin (AOPPs-RSA) in vitro. Exposure of chondrocyte to AOPPs activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and increased expression of NADPH oxidase subunits, which was mediated by receptor for advanced glycation end products (RAGE), but not scavenger receptor CD36. Moreover, AOPPs challenge triggered NADPH oxidase-dependent ROS generation which induced mitochondrial dysfunction and endoplasmic reticulum stress resulted in activation of caspase family that eventually lead to apoptosis. Lastly, blockade of RAGE, instead of CD36, largely attenuated these signals. Our study demonstrated first time that AOPPs induce chondrocyte apoptosis via RAGE-mediated and redox-dependent intrinsic apoptosis pathway in vitro. These data implicates that AOPPs may represent a novel pathogenic factor that contributes to RA progression. Targeting AOPPs-triggered cellular mechanisms might emerge as a promising therapeutic option for patients with RA.
促炎细胞因子诱导的软骨细胞凋亡是类风湿关节炎（RA）进展过程中软骨破坏的主要原因。晚期氧化蛋白产物（AOPPs）作为一种新型促炎介质，已证实在RA患者体内蓄积。然而，AOPPs蓄积对软骨细胞凋亡的影响及其相关细胞机制仍不清楚。本研究表明，与正常大鼠相比，RA大鼠血浆中AOPPs的生成增强。然后，在体外用AOPPs修饰的大鼠血清白蛋白（AOPPs-RSA）处理软骨细胞。软骨细胞暴露于AOPPs会激活烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶并增加NADPH氧化酶亚基的表达，这是由晚期糖基化终产物受体（RAGE）介导的，而非清道夫受体CD36。此外，AOPPs刺激引发NADPH氧化酶依赖性活性氧生成，诱导线粒体功能障碍和内质网应激，导致半胱天冬酶家族激活，最终导致细胞凋亡。最后，阻断RAGE而非CD36可在很大程度上减弱这些信号。我们的研究首次证明，AOPPs在体外通过RAGE介导的氧化还原依赖性内源性凋亡途径诱导软骨细胞凋亡。这些数据表明，AOPPs可能是导致RA进展的一种新型致病因素。针对AOPPs触发的细胞机制可能成为RA患者一种有前景的治疗选择。
