TIMP1 regulates ferroptosis in osteoblasts by inhibiting TFRC ubiquitination: an in vitro and in vivo study

作者：Bo Peng, Zhiwei Feng, Ao Yang, Jinmin Liu, Jinwen He, XU Li-hu, Cong Tian, Xiaoyun Sheng, Yaobin Wang, Rongjin Chen, Xingwen Wang, Xiaojun Ren, Bin Geng, Yayi Xia · 发表于：Molecular Medicine · 年份：2024 · DOI：10.1186/s10020-024-01000-9 · 被引用次数：10 · 研究领域：Ferroptosis and cancer prognosis、Bone Metabolism and Diseases、Genetic Associations and Epidemiology

BACKGROUND: In clinical practice, alterations in the internal environment of type 2 diabetes can significantly affect bone quality. While the increased risk of fractures among diabetic patients is well-established, the precise mechanisms by which hyperglycemia influences bone quality remain largely unclear. METHODS: Western blotting, immunohistochemistry (IHC), and micro-CT were used to examine ferroptosis-related protein expression and bone morphology changes in the bone tissues of type 2 diabetic mice. The CCK8 assay determined the optimal conditions for inducing ferroptosis in osteoblasts by high glucose and high fat (HGHF). Ferroptosis phenotypes in osteoblasts were analyzed using flow cytometry, Western blotting, and two-photon laser confocal microscopy. Transcriptomic sequencing of the control and HGHF groups, followed by bioinformatic analysis, identified and validated key genes. TIMP1 was knocked down in osteoblasts to assess its impact on ferroptosis, while TFRC expression was inhibited and activated to verify the role of TIMP1 in regulating ferroptosis through TFRC. The therapeutic effect of TIMP1 inhibition on osteoporosis was evaluated in a type 2 diabetic mouse model. RESULTS: The expression of TIMP1 is increased in type 2 diabetic osteoporosis. In vitro, TIMP1 knockout inhibited ferroptosis in osteoblasts induced by high glucose and high fat (HGHF). However, overexpression of TFRC reversed the ferroptosis inhibition caused by TIMP1 knockout. Suppression of TIMP1...