VDR activation attenuates osteoblastic ferroptosis and senescence by stimulating the Nrf2/GPX4 pathway in age-related osteoporosis.
VDR activation attenuates osteoblastic ferroptosis and senescence by stimulating the Nrf2/GPX4 pathway in age-related osteoporosis.
复制标题
在年龄相关性骨质疏松症中，维生素D受体（VDR）激活通过刺激Nrf2/GPX4通路减轻成骨细胞铁死亡和衰老。
DOI：
10.1016/j.freeradbiomed.2022.11.013
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发表时间：
2022-11
影响因子：
7.4
通讯作者：
Pingcui Xu;Bingfeng Lin;Xuehui Deng;Kai Huang;Yan Zhang;Nan Wang
中科院分区：
文献类型：
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作者：
Pingcui Xu;Bingfeng Lin;Xuehui Deng;Kai Huang;Yan Zhang;Nan Wang
上睑下垂在骨质疏松症病理中起重要作用。本研究探讨了维生素D受体（VDR）激活是否能通过抗铁下垂机制预防老年性骨质疏松症。采用d-半乳糖（D-gal）诱导小鼠和vdr基因敲除小鼠进行体内研究。VDR激活剂（1,25(OH)2D3）减轻了d -gal诱导的骨的衰老和铁下垂，如衰老相关分泌表型基因下调、线粒体形态改善、谷胱甘肽升高和脂质过氧化标志物（丙二醛和4-羟基壬烯醛）降低所示。采用成骨前MC3T3-E1细胞和原代大鼠成骨细胞进行体外研究。1,25(OH) 2d3或铁下垂抑制剂（铁抑素-1）治疗可下调d -gal诱导的成骨细胞的细胞衰老标志物。机制上，1,25(OH) 2d3激活了VDR及其下游核因子红细胞2相关因子2 (Nrf2)/谷胱甘肽过氧化物酶4 （GPX4）信号通路，导致脂质过氧化下调。Nrf2敲低或加入GPX4抑制剂（RSL-3）可阻断1,25(OH) 2d3对d -gal诱导的铁下垂和衰老的保护作用。VDR敲除抑制了成骨细胞中1,25(OH) 2d3诱导的Nrf2/GPX4通路的激活。蛋白质组学和免疫荧光分析证实，在vdr敲除小鼠中发生了铁凋亡和Nrf2/GPX4通路的抑制。我们的数据表明，铁下垂在与年龄相关的骨质疏松症中起重要作用。VDR激活通过刺激Nrf2/GPX4信号通路减轻成骨细胞铁下垂。
Ferroptosis plays an essential role in the pathology of osteoporosis. This study investigated whether vitamin D receptor (VDR) activation could protect against age-related osteoporosis through an anti-ferroptosis mechanism.d-galactose (D-gal)-induced mice and VDR-knockout mice were used in thein-vivostudy. The VDR activator (1,25(OH)2D3) attenuated senescence and ferroptosis in the D-gal-induced bone, as illustrated by downregulated senescence-associated secretory phenotype genes, improved mitochondrial morphology, elevated glutathione, and decreased lipid peroxidation markers (malondialdehyde and 4-hydroxynonenal). The pre-osteoblast MC3T3-E1 cells and primary rat osteoblasts were applied in thein-vitrostudies. 1,25(OH)2D3or ferroptosis inhibitor (ferrostatin-1) treatment downregulated the cellular senescence markers in D-gal-induced osteoblasts. Mechanistically, 1,25(OH)2D3activated the VDR and its downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway, resulting in the downregulation of lipid peroxidation. Nrf2 knockdown or addition of GPX4 inhibitor (RSL-3) blocked the protective effect of 1,25(OH)2D3against D-gal-induced ferroptosis and senescence. VDR knockdown impeded the 1,25(OH)2D3-induced activation of Nrf2/GPX4 pathway in osteoblasts. Proteomics and immunofluorescence analysis confirmed that ferroptosis and suppression of the Nrf2/GPX4 pathway occurred in VDR-knockout mice. Our data demonstrated that ferroptosis played an essential role in age-related osteoporosis. The VDR activation attenuated osteoblast ferroptosis via stimulating the Nrf2/GPX4 signaling pathway.