7-ketocholesterol enhances autophagy via the ROS-TFEB signaling pathway in osteoclasts

Oxysterols play a critical role in human health and diseases associated with high cholesterol and oxidative stress. Given that a positive correlation was observed between cholesterol and collagen type 1 fragment (CTX-1) or serum reactive oxygen species (ROS) in humans, we hypothesized that oxidized cholesterol metabolites may participate in cholesterol-induced bone loss. Therefore, this study aimed to identify the metabolite responsible for cholesterol-associated bone loss and evaluate its effect on osteoclasts (OCs) leading to bone loss. An atherogenic diet in mice increased the levels of the oxysterol, 7-ketocholesterol (7-KC) in bone, as well as serum ROS. 7-KC increased the number and activity of OCs by enhancing autophagy via the ROS-transcription factor EB signaling pathway. These findings suggest that 7-KC acts as a cholesterol metabolite and is at least partially responsible for cholesterol-induced bone loss by inducing autophagy in OCs.