Targeting ferroptosis suppresses osteocyte glucolipotoxicity and alleviates diabetic osteoporosis  

作　　者：Yiqi Yang Yixuan Lin Minqi Wang Kai Yuan Qishan Wang Pei Mu Jingke Du Zhifeng Yu Shengbing Yang Kai Huang Yugang Wang Hanjun Li Tingting Tang 

机构地区：[1]Shanghai Key Laboratory of Orthopaedic Implants,Department of Orthopaedic Surgery,Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,China [2]Department of Bone and Joint Surgery,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,China [3]Department of Orthopaedics,Shanghai Jiangong Hospital,Shanghai,China [4]Department of Trauma Surgery,Department of Orthopedics,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,China [5]Clinical Stem Cell Research Center,Renji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,Chin

出　　处：《Bone Research》2022年第3期509-523,共15页骨研究（英文版）

基　　金：supported by National Natural Science Foundation of China(NSFC)grants 92068205,81802679,and 82002328;supported by China Postdoctoral Science Foundation grants 2018M632136 and 2019T120348。

摘　　要：Diabetic osteoporosis(DOP) is the leading complication continuously threatening the bone health of patients with diabetes. A key pathogenic factor in DOP is loss of osteocyte viability. However, the mechanism of osteocyte death remains unclear. Here, we identified ferroptosis, which is iron-dependent programmed cell death, as a critical mechanism of osteocyte death in murine models of DOP. The diabetic microenvironment significantly enhanced osteocyte ferroptosis in vitro, as shown by the substantial lipid peroxidation, iron overload, and aberrant activation of the ferroptosis pathway. RNA sequencing showed that heme oxygenase-1(HO-1) expression was notably upregulated in ferroptotic osteocytes. Further findings revealed that HO-1 was essential for osteocyte ferroptosis in DOP and that its promoter activity was controlled by the interaction between the upstream NRF2 and c-JUN transcription factors. Targeting ferroptosis or HO-1 efficiently rescued osteocyte death in DOP by disrupting the vicious cycle between lipid peroxidation and HO-1 activation, eventually ameliorating trabecular deterioration. Our study provides insight into DOP pathogenesis, and our results provide a mechanism-based strategy for clinical DOP treatment.

关 键 词：PEROXIDATION OSTEOPOROSIS DIABETIC 

分 类 号：R587.2[医药卫生—内分泌] R580[医药卫生—内科学]