Geniposide Augments Apoptosis in Fibroblast-like Synoviocytes by restoring Hypoxia-enhanced JNK-BNIP3-mediated Autophagy

Objective: As the main effector cells of chronic inflammation and hyperplasia of synovium, fibroblast-like synoviocytes (FLSs) show abnormal proliferation and insufficient apoptosis in hypoxic microenvironment, which is due to the increase of BNIP3-mediated autophagy. This study aimed to explore the mechanism of geniposide (GE) on hypoxia-induced hyper-proliferative FLSs with a focus on autophagy and JNK-BNIP3 pathway. Materials and methods The dynamic changes of autophagy and apoptosis and the expression of hypoxia related proteins in adjuvant arthritis (AA) rats were detected by immunohistochemistry and Western blot. The proliferation, autophagy, apoptosis and mitochondrial state of FLSs were detected by CCK-8, flow cytometry, immunofluorescence and transmission electron microscopy, respectively. Results The excessive accumulation of BNIP3 in synovium of AA rats was accompanied by inhibition of apoptosis and increase of autophagy. GE inhibited the expression of BNIP3, enhanced apoptosis and decreased autophagy, and improved chronic inflammation and hyperplasia of synovium. The amount of autophagy under different oxygen concentrations was the key to mediate the different survival rates of FLSs, and the inhibition of autophagy triggered apoptosis. GE suppresssed the proliferation of FLSs, and down-regulated autophagy, leading to the accumulation of ROS and the decrease of mitochondrial membrane potential (MMP), induced the increase of apoptosis, and suppressed the accumulation of BNIP3 and the hyperphosphorylation of JNK. Conclusions GE inhibited autophagy by restoring the hypoxia-induced activated JNK-BNIP3 pathway, inducing mitochondrial oxidative damage, augmented apoptosis and decreased survival rate of FLSs.