SIRT6 Prevents Glucocorticoid-Induced Osteonecrosis of the Femoral Head in Rats

Abstract

Objective. Glucocorticoid-induced osteonecrosis of the femoral head is one of the most common causes of nontraumatic osteonecrosis of the femoral head, but its exact pathogenesis remains unclear. The aim of this study was to investigate the role of SIRT6 in the maintenance of bone tissue morphology and structure, intravascular lipid metabolism, and its potential molecular mechanism in glucocorticoid-induced osteonecrosis of the femoral head. Methods. SIRT6 adenovirus was transfected into GIONFH in rats. The microstructure of rat bone was observed by micro-CT and histological staining, and the expression of bone formation-related proteins and angiogenesis-related factors was determined through western blot and immunohistochemistry. Alkaline phosphatase activity, alizarin red staining, and the expression levels of Runx2 and osteocalcin were used to evaluate the osteogenic potential. And in vitro tube formation assay and immunofluorescence were used to detect the ability of endothelial cell angiogenesis. Results. Dexamethasone significantly inhibited osteoblast differentiation, affected bone formation, and destroyed microvessel formation, increased the intracellular Fe2+ and ROS levels and induced the occurrence of ferroptosis. SIRT6 can inhibit ferroptosis and restore the ability of bone formation and angiogenesis. Conclusion. SIRT6 can inhibit the occurrence of ferroptosis, reduce the damage of vascular endothelium, and promote osteogenic differentiation, so as to prevent the occurrence of osteonecrosis of the femoral head.

Inhibition of SIRT6 aggravates p53-mediated ferroptosis in acute lung injury in mice

“…Melatonin has been shown to regulate SIRT6, thereby inhibiting ferroptosis and delaying age-related cataract [ 33 ]. SIRT6 has been reported to prevent osteonecrosis of the femoral head by inhibiting ferroptosis [ 15 ]. In the present study, the inhibition of SIRT6 was found to enhance LPS-induced ferroptosis in ALI, thereby indicating that ferroptosis is an essential factor involved in the SIRT6-mediated protection against ALI.…”

“…SIRT6 has been shown to exert protective effects in various diseases [ 13 , 14 ]; however, the role of SIRT6 in ALI remains unclear. Recent studies have demonstrated that SIRT6 exerts its biological effects by regulating p53-mediated ferroptosis [ 15 , 16 ]. In the present study, we investigate the protective effect of SIRT6 against LPS-induced ALI by the regulation of p53-mediated ferroptosis.…”

The roles of sirtuins in ferroptosis

“…Recently, SIRT6 has been demonstrated to inhibit nuclear transcription of NF-κB and inactivate NF-κB to facilitate ferroptosis in pancreatic cancer, thereby exerting anti-tumor effects ( Gong et al, 2022 ). Fang et al (2022) demonstrated that SIRT6 overexpression could reverse the decreased levels of GPX4, SLC7A11, and GSH and reduce the cellular accumulation of MDA and ROS to inhibit ferroptosis, ultimately restoring bone formation and angiogenesis and relieving femoral head necrosis. Mi et al demonstrated that melatonin inhibited ferroptosis in rat lens epithelial cells through SIRT6/p-NRF2/GPX4 and SIRT6/NCOA4/FTH1 pathways, neutralized lipid peroxidation toxicity, and delayed the formation of cataract caused by ultraviolet rays exposure ( Mi et al, 2023 ).…”

Serum glutathione peroxidase 4 as a novel biomarker for nontraumatic osteonecrosis of the femoral head: A retrospective case-control study

“…Recently, an experimental study observed a decreased expression of GPx4 protein in the femoral head of rat model of osteonecrosis. [ 7 ] This highlights the crucial role of GPx4 in the pathogenesis of NONFH.…”