活性氧（ROS）的产生是无机磷酸盐（Pi）诱导成骨细胞矿化的潜在机制。,Free Radical Biology and Medicine

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活性氧（ROS）的产生是无机磷酸盐（Pi）诱导成骨细胞矿化的潜在机制。
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2020-04-21 , DOI: 10.1016/j.freeradbiomed.2020.04.008
Sana Khalid ₁ , Hajime Yamazaki ₁ , Mairobys Socorro ₁ , Daisy Monier ₁ , Elia Beniash ₂ , Dobrawa Napierala ₂

Affiliation

活性氧 (ROS) 是氧代谢的天然副产品。在生理水平上，ROS 调节多种细胞过程，如增殖、迁移和分化。ROS水平升高与炎症和血管钙化等病理状况有关，它们会引起细胞毒性作用。ROS 的这些对比结果也在成骨前体细胞中得到报道。然而，ROS 在定向成骨细胞中的作用尚未得到研究。细胞外磷酸盐 (Pi) 的细胞毒性和生理效应也已得到证实。具体而言，在定型成骨细胞中，Pi 刺激其主要功能（矿化），但在成骨前体细胞和内皮细胞中，Pi 具有细胞毒性。有趣的是，Pi 细胞毒性作用与病理性血管矿化中 ROS 的产生有关。在这项研究中，我们在定向成骨细胞的矿化功能背景下研究了 Pi 升高和 ROS 产生之间的分子机制联系。使用定向成骨细胞、17IIA11 成牙本质细胞样细胞和 MLO-A5 成骨细胞系，我们发现 Pi 可以增强细胞内 ROS 的产生。此外，结合矿化测定和基因表达分析，我们确定 Pi 诱导的细胞内 ROS 支持生理矿化过程。相反，以 H2O2 形式提供的外源 ROS 对成骨细胞有害。通过比较细胞外 ROS 和 Pi 诱导的分子信号级联，我们发现了决定 ROS 对成骨细胞的生理作用和毒性作用的信号传导途径的差异。具体来说，虽然细胞外和 Pi 诱导的细胞内 ROS 都利用 Erk1/2 信号传导介质，但只有细胞外 ROS 诱导与细胞死亡相关的应激激活的丝裂原激活蛋白激酶 P38 和 JNK。总之，我们的结果揭示了 ROS 通过分子途径在 Pi 诱导的矿化中发挥的生理作用，这与 ROS 诱导的细胞毒性作用不同。

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Reactive oxygen species (ROS) generation as an underlying mechanism of inorganic phosphate (Pi)-induced mineralization of osteogenic cells.

Reactive Oxygen Species (ROS) are a natural byproduct of oxygen metabolism. At physiological levels, ROS regulate multiple cellular processes like proliferation, migration, and differentiation. Increased levels of ROS are associated with pathological conditions, such as inflammation and vascular calcification, where they elicit cytotoxic effects. These contrasting outcomes of ROS have also been reported in osteogenic precursor cells. However, the role of ROS in committed osteogenic cells has not been investigated. Cytotoxic and physiologic effects have also been demonstrated for extracellular phosphate (Pi). Specifically, in committed osteogenic cells Pi stimulates their major function (mineralization), however in osteogenic precursors and endothelial cells Pi cytotoxicity has been reported. Interestingly, Pi cytotoxic effects have been associated with ROS production in the pathological vascular mineralization. In this study, we investigated a molecular mechanistic link between elevated Pi and ROS production in the context of the mineralization function of committed osteogenic cells. Using committed osteogenic cells, 17IIA11 odontoblast-like cell and MLO-A5 osteoblast cell lines, we have unveil that Pi enhances intracellular ROS production. Furthermore, using a combination of mineralization assays and gene expression analyses, we determined that Pi-induced intracellular ROS supports the physiological mineralization process. In contrast, the exogenous ROS, provided in a form of H2O2, was detrimental for osteogenic cells. By comparing molecular signaling cascades induced by extracellular ROS and Pi, we identified differences in signaling routes that determine physiologic versus toxic effect of ROS on osteogenic cells. Specifically, while both extracellular and Pi-induced intracellular ROS utilize Erk1/2 signaling mediator, only extracellular ROS induces stress-activated mitogen-activated protein kinases P38 and JNK that are associated with cell death. In summary, our results uncovered a physiological role of ROS in the Pi-induced mineralization through the molecular pathway that is distinct from ROS-induced cytotoxic effects.

更新日期：2020-04-22

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