Cadmium exposure induces osteoporosis through cellular senescence, associated with activation of NF-κB pathway and mitochondrial dysfunction
Cadmium exposure induces osteoporosis through cellular senescence, associated with activation of NF-κB pathway and mitochondrial dysfunction
复制标题
镉暴露通过细胞衰老诱发骨质疏松症，与 NF-κB 通路激活和线粒体功能障碍有关
DOI：
10.1016/j.envpol.2021.118043
复制
发表时间：
2021-09-01
影响因子：
8.9
通讯作者：
Xu, Baoshan
中科院分区：
文献类型：
--
作者：
Luo, Huigen;Gu, Renjie;Xu, Baoshan
镉（Cd）是一种常见的重金属毒物，来源于多种农业和工业污染源。镉的吸收主要通过镉污染的食物和水，并在很大程度上，通过吸入镉污染的空气和吸烟。流行病学数据表明，职业或环境接触镉增加骨质疏松症和自发性骨折，如itai-itai病的健康风险。然而，镉暴露对骨损伤的直接影响和潜在机制在很大程度上是未知的。我们采用原代骨髓间充质干细胞（BMMSCs），发现镉通过过度激活NF-κ B B信号通路，显著诱导BMMSCs细胞衰老。通过衰老相关分泌表型（SASP）的产生、细胞周期停滞和p21/p53/p16（INK4a）蛋白表达的上调来确定细胞衰老的增加。此外，镉损害BMMSCs的成骨分化和增加脂肪形成，并显著诱导细胞衰老相关的缺陷，如线粒体功能障碍和DNA损伤。采用SD大鼠慢性染镉实验，观察镉对大鼠体内脂肪细胞数量的影响，以及对骨髓矿化组织的影响。有趣的是，我们观察到，镉暴露显着延缓颅骨缺损手术后的骨修复和再生。值得注意的是，褪黑激素的预处理能够部分防止镉诱导的一些衰老相关的缺陷，包括线粒体功能障碍和DNA损伤的BMMSCs。虽然镉激活哺乳动物雷帕霉素靶蛋白（mTOR）通路，雷帕霉素只能部分改善镉诱导的细胞凋亡，而不是细胞衰老表型的BMMSCs。此外，选择性NF-κ B抑制剂适度减轻镉引起的BMMSCs衰老相关缺陷。本研究揭示了镉在骨质疏松和骨老化中的作用和机制，为改善镉暴露的危害提供了新的途径。
Cadmium (Cd) is a heavy metal toxicant as a common pollutant derived from many agricultural and industrial sources. The absorption of Cd takes place primarily through Cd-contaminated food and water and, to a significant extent, via inhalation of Cd-contaminated air and cigarette smoking. Epidemiological data suggest that occupational or environmental exposure to Cd increases the health risk for osteoporosis and spontaneous fracture such as itai-itai disease. However, the direct effects and underlying mechanism(s) of Cd exposure on bone damage are largely unknown. We used primary bone marrow-derived mesenchymal stmmal cells (BMMSCs) and found that Cd significantly induced BMMSC cellular senescence through over-activation of NF-kappa B signaling pathway. Increased cell senescence was determined by production of senescence-associated secretory phenotype (SASP), cell cycle arrest and upregulation of p21/p53/p16(INK4a) protein expression. Additionally, Cd impaired osteogenic differentiation and increased adipogenesis of BMMSCs, and significantly induced cellular senescenceassociated defects such as mitochondrial dysfunction and DNA damage. Sprague-Dawley (SD) rats were chronically exposed to Cd to verify that Cd significantly increased adipocyte number, and decreased mineralization tissues of bone marrow in vivo. Interestingly, we observed that Cd exposure remarkably retarded bone repair and regeneration after operation of skull defect. Notably, pretreatment of melatonin is able to partially prevent Cd-induced some senescence-associated defects of BMMSCs including mitochondrial dysfunction and DNA damage. Although Cd activated mammalian target of rapamycin (mTOR) pathway, rapamycin only partially ameliorated Cd-induced cell apoptosis rather than cellular senescence phenotypes of BMMSCs. In addition, a selective NF-kappa B inhibitor moderately alleviated Cd-caused the senescence-related defects of the BMMSCs. The study shed light on the action and mechanism of Cd on osteoporosis and bone ageing, and may provide a novel option to ameliorate the harmful effects of Cd exposure.