Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Chuoku, Kumamoto, Japan.
FEBS J. 2013 Apr;280(7):1617-29. doi: 10.1111/febs.12170. Epub 2013 Mar 1.
Mammalian cells attempt to maintain their homeostasis under endoplasmic reticulum (ER) stress. If the stress cannot be alleviated, cells are led to apoptosis through induction of C/EBP homologous protein (CHOP). ER stress is provoked in osteoarthritis chondrocytes, and intracellular accumulation of advanced glycation end products (AGEs) in chondrocytes is a possible cause. To clarify the role of intracellular AGE accumulation in chondrocytes, the present study investigated the effect of intracellular AGE accumulation on ER stress and apoptosis by in vitro and in vivo analysis. Intracellular AGE accumulation induced by AGE precursors caused apoptosis, induced expression of ER stress markers, and led to co-localization of AGEs with glucose-regulated protein 78, leading to formation of high-molecular-weight complexes in cultured chondrocytes. These reactions were inhibited by an AGE formation inhibitor. CHOP deletion inhibited apoptosis induced by intracellular AGE accumulation. In vivo intracellular AGE accumulation induced by intra-articular injection of AGE precursors caused ER stress and apoptosis in chondrocytes and led to degradation of articular cartilage. Additionally, intracellular AGE accumulation increased the degree of cartilage degradation in an osteoarthritis model. These data indicate that intracellular accumulation of AGEs induces modification of unfolded protein response-related protein by AGEs and apoptosis via ER stress in chondrocytes. Moreover, the in vivo study showed that intracellular AGE accumulation in chondrocytes is involved in the occurrence and progression of osteoarthritis through ER stress. Thus, research on mechanisms of apoptosis via ER stress induced by intracellular AGE accumulation in chondrocytes will lead to a new understanding of osteoarthritis pathology.
哺乳动物细胞试图在内质网 (ER) 应激下维持其体内平衡。如果应激不能缓解，细胞就会通过诱导 C/EBP 同源蛋白 (CHOP) 而导致凋亡。骨关节炎软骨细胞中存在 ER 应激，细胞内晚期糖基化终产物 (AGEs) 的积累是一个可能的原因。为了阐明软骨细胞内 AGE 积累的作用，本研究通过体外和体内分析研究了细胞内 AGE 积累对 ER 应激和凋亡的影响。AGE 前体诱导的细胞内 AGE 积累诱导细胞凋亡，诱导 ER 应激标志物的表达，并导致 AGE 与葡萄糖调节蛋白 78 共定位，导致培养软骨细胞中形成高分子量复合物。这些反应被 AGE 形成抑制剂抑制。CHOP 缺失抑制了细胞内 AGE 积累诱导的凋亡。关节内注射 AGE 前体引起的体内细胞内 AGE 积累诱导软骨细胞 ER 应激和凋亡，并导致关节软骨降解。此外，细胞内 AGE 积累增加了骨关节炎模型中软骨降解的程度。这些数据表明，细胞内 AGE 积累通过 ER 应激诱导软骨细胞中未折叠蛋白反应相关蛋白的修饰和凋亡。此外，体内研究表明，软骨细胞内 AGE 积累通过 ER 应激参与骨关节炎的发生和进展。因此，对软骨细胞内 AGE 积累诱导的 ER 应激导致凋亡的机制的研究将为骨关节炎病理学提供新的认识。
