title: 7-ketocholesterol induces apoptosis of MC3T3-E1 cells associated with reactive oxygen species generation, endoplasmic reticulum stress and caspase-3/7 dependent pathway.
abstract: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of bone fractures without reduction of bone mineral density. The cholesterol oxide 7-ketocholesterol (7KCHO) has been implicated in numerous diseases such as atherosclerosis, Alzheimer's disease, Parkinson's disease, cancer, age-related macular degeneration and T2DM. In the present study, 7KCHO decreased the viability of MC3T3-E1 cells, increased reactive oxygen species (ROS) production and apoptotic rate, and upregulated the caspase-3/7 pathway. Furthermore, these effects of 7KCHO were abolished by pre-incubation of the cells withN-acetylcysteine (NAC), an ROS inhibitor. Also, 7KCHO enhanced the mRNA expression of two endoplasmic reticulum (ER) stress markers; CHOP and GRP78, in MC3T3-E1 cells. Pre-incubation of the cells with NAC suppressed the 7KCHO-induced upregulation of CHOP, but not GRP78. In conclusion, we demonstrated that 7KCHO induced apoptosis of MC3T3-E1 cells associated with ROS generation, ER stress, and caspase-3/7 activity, and the effects of 7KCHO were abolished by the ROS inhibitor NAC. These findings may provide new insight into the relationship between oxysterol and pathophysiology of osteoporosis seen in T2DM.
authors.affiliation: Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, 564-1, Shimoshizu, Sakura City, Chiba 285-8741, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, 564-1, Shimoshizu, Sakura City, Chiba 285-8741, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ishihara
authors.affiliation: Center of Endocrinology and Metabolism, Shin-Oyama City Hospital, 1-1-5, Wakagi-cho, Oyama City, Tochigi 323-0028, Japan.
authors.forename: Daiji
authors.initials: D
authors.lastname: Nagayama
authors.affiliation: Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, 564-1, Shimoshizu, Sakura City, Chiba 285-8741, Japan.
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Saiki
authors.affiliation: Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, 564-1, Shimoshizu, Sakura City, Chiba 285-8741, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Tatsuno
keywords: 7-ketocholesterol; Apoptosis; MC3T3-E1 cells; N-acetylcysteine (NAC); Reactive oxygen species (ROS)