Reactive Oxygen Species Control Osteoblast Apoptosis through SIRT1/PGC-1α/P53^Lys382 Signaling, Mediating the Onset of Cd-Induced Osteoporosis

Abstract

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 Cd-induced ROS release. SIRT1 overexpression in vivo and in vitro dampened PGC-1α 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.

Allicin Alleviates Mitochondrial Dysfunction in Acrylamide-Induced Rat Kidney Involving the Regulation of SIRT1

“…Current studies have highlighted the crucial role of SIRT1 as an upstream target of p53. For instance, SIRT1 overexpression inhibits p53 acetylation in response to p53-dependent apoptosis. − SIRT1 can suppress p53 acetylation and reverse its combination with the DPR1 promoter, reduce mPTP opening, increase the ATP content, and inhibit caspase 3 activation, thereby inhibiting mitochondrial fission and ultimately attenuating apoptosis. ,, In our results, allicin decreased the level of p53 acetylation, and laser confocal observation further confirmed that the interaction degree of SIRT1 with ace-p53 was dose-dependently restored by allicin, indicating that SIRT1 attenuated mitochondrial apoptosis by crosstalk with p53.…”

TMBIM6 deficiency leads to bone loss by accelerating osteoclastogenesis

“…We also found that depletion of TMBIM6 suppressed the proliferation of preosteoblasts, which in turn led to the inhibition of osteoblast differentiation. Several studies have shown that ROS can prevent osteoblast differentiation by inducing apoptosis [ [61] , [62] , [63] ]. Our study, along with others, has shown that TMBIM6 reduces ROS levels (as shown in Fig.…”

Modulation of the Adverse Health Effects of Environmental Cadmium Exposure by Zinc and Its Transporters

“…This may reflect a very high sensitivity of bone to mitochondrial effects of Cd, leading to enhanced ROS production and oxidative damage. Bone tissues from patients with osteoporosis had higher Cd levels, compared to controls without osteoporosis [143].…”