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Intracellular accumulation of advanced glycation end products induces apoptosis via endoplasmic reticulum stress in chondrocytes
Author(s) -
Yamabe Soichiro,
Hirose Jun,
Uehara Yusuke,
Okada Tatsuya,
Okamoto Nobukazu,
Oka Kiyoshi,
Taniwaki Takuya,
Mizuta Hiroshi
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12170
Subject(s) - intracellular , unfolded protein response , endoplasmic reticulum , microbiology and biotechnology , apoptosis , glycation , chemistry , advanced glycation end product , cartilage , biology , biochemistry , anatomy , receptor
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 ( AGE s) 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 AGE s 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 AGE s induces modification of unfolded protein response‐related protein by AGE s 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.