Lansoprazole-induced osteoporosis via the IP3R- and SOCE-mediated calcium signaling pathways.
Lansoprazole-induced osteoporosis via the IP3R- and SOCE-mediated calcium signaling pathways.
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兰索拉唑通过 IP3R 和 SOCE 介导的钙信号通路诱导骨质疏松
DOI：
10.1186/s10020-022-00448-x
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发表时间：
2022-02-19
期刊：
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Cheng Z;Liu Y;Ma M;Sun S;Ma Z;Wang Y;Yu L;Qian X;Sun L;Zhang X;Liu Y;Wang Y
许多临床研究表明质子泵抑制剂（PPI）与骨质疏松症或骨折之间存在相关性。本研究的目的是建立长期口服PPI的小鼠模型，以验证PPI是否引起骨代谢损伤，并研究PPI对MC 3 T3-E1小鼠成骨细胞影响的相关分子机制。使用兰索拉唑诱导的骨丢失模型研究PPI的损伤作用。在体内，使用免疫组织化学、苏木精-伊红（HE）染色、显微CT分析和血液生化分析来评价兰索拉唑对小鼠骨损伤的影响。在体外，通过CCK-8测定、EdU测定、流式细胞术、激光共聚焦显微镜、膜片钳、逆转录-定量聚合酶链反应和蛋白质印迹法研究兰索拉唑对MC 3 T3-E1细胞及其相关信号通路的影响。ICR小鼠灌胃兰索拉唑6个月后，micro-CT结果显示，与溶媒组相比，高剂量组骨密度明显降低（P < 0.05），骨微结构逐渐退化。骨血清生化分析显示血钙、血磷均降低（P < 0.01）。我们发现，长期给予兰索拉唑会损害小鼠的骨骼功能。在体外实验中，我们发现兰索拉唑（LPZ）可引起MC 3 T3-E1细胞内钙超载，导致细胞凋亡，而IP 3R钙释放通道和SOCE通路抑制剂2-APB可有效阻断LPZ引起的钙超载，从而保护细胞活力。长期给予LPZ可诱导小鼠出现骨质疏松症状，LPZ以浓度依赖性方式触发成骨细胞钙增加。细胞内钙（[Ca 2 +]i）持续高浓度，从而引起内质网应激（ERS），诱导成骨细胞凋亡。
Many clinical studies have shown a correlation between proton pump inhibitors (PPIs) and osteoporosis or fractures. The purpose of this study was to establish a murine model of chronic oral PPI administration to verify whether PPIs caused bone metabolic impairment and investigate the relevant molecular mechanism underlying the effects of PPIs on MC3T3-E1 murine osteoblasts. A lansoprazole-induced bone loss model was used to investigate the damaging effects of PPIs. In vivo, immunohistochemistry, Hematoxylin–Eosin (HE) staining, micro-CT analysis, and blood biochemical analyses were used to evaluate the effect of lansoprazole on bone injury in mice. In vitro, the effects of lansoprazole and related signaling pathways in MC3T3-E1 cells were investigated by CCK-8 assays, EdU assays, flow cytometry, laser confocal microscopy, patch clamping, reverse transcription-quantitative polymerase chain reaction and Western blotting. After 6 months of lansoprazole gavage in ICR mice, the micro-CT results showed that compared with that in the vehicle group, the bone mineral density (BMD) in the high-dose group was significantly decreased (P < 0.05), and the bone microarchitecture gradually degraded. Biochemical analysis of bone serum showed that blood calcium and phosphorus were both decreased (P < 0.01). We found that long-term administration of lansoprazole impaired skeletal function in mice. In vitro, we found that lansoprazole (LPZ) could cause calcium overload in MC3T3-E1 cells leading to apoptosis, and 2-APB, an inhibitor of IP3R calcium release channel and SOCE pathway, effectively blocked increase in calcium caused by LPZ, thus protecting cell viability. Longterm administration of LPZ induced osteoporotic symptoms in mice, and LPZ triggered calcium increases in osteoblasts in a concentration-dependent manner. Intracellular calcium ([Ca2+]i) persisted at a high concentration, thereby causing endoplasmic reticulum stress (ERS) and inducing osteoblast apoptosis.
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影响因子：
7
作者：
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