Reactive Oxygen Species Control Osteoblast Apoptosis through SIRT1/PGC-1?/P53Lys382 Signaling, Mediating the Onset of Cd-Induced Osteoporosis

The imbalance between osteogenesis and osteoclastogenesis is a feature of bone metabolic disease. Cadmium (Cd) exposure causes human bone loss and osteoporosis (OP) through bioaccumulation of the food chain. However, the impact of Cd on bone tissues and the underlying molecular mechanisms are not well-characterized. In the current study, we found that the Cd concentration in bone tissues of OP patients was higher than normal subjects; meanwhile, the nuclear silent information regulator of transcription 1 (SIRT1) protein expression level was significantly decreased, which is a new star molecule to treat OP. It is further revealed that SIRT1 activation markedly reprograms bone metabolic and stress-response pathways that incline with osteoblast (OB) apoptosis. Suppressing reactive oxygen species (ROS) release with N-acetyl-L-cysteine (NAC) abolished Cd-induced reduction of SIRT1 protein, deacetylation of P53, OB apoptosis, and attenuated OP. Conversely, overexpression of SIRT1 suppressed Cdinduced ROS release. SIRT1 overexpression in vivo and in vitro dampened PGC-1 alpha protein, acetylation of P53 at lysine 382, and caspase-dependent apoptosis. These results reveal that ROS/SIRT1 controls P53 acetylation and coordinates OB apoptosis involved in the onset of OP.

Automated summary

Cadmium exposure in bone tissues leads to higher Cd concentration in osteoporosis (OP) patients compared to normal subjects. This exposure also decreases the expression level of SIRT1 protein, exacerbating osteoblast apoptosis and bone resorption.