Orientin 通过抑制 ROS 产生来抑制破骨细胞生成并改善卵巢切除引起的骨质疏松症,Food Science & Nutrition

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Orientin 通过抑制 ROS 产生来抑制破骨细胞生成并改善卵巢切除引起的骨质疏松症
Food Science & Nutrition ( IF 3.5 ) Pub Date : 2023-06-28 , DOI: 10.1002/fsn3.3516
Yan Zheng _{1,

2} , Xing Wang ₁ , Ya-Jing Pan ₁ , Xiao-Feng Shi ₁ , Lei Yang ₃ , Yong-Liang Lou ₁

Affiliation

破骨细胞的异常分化是骨质疏松症发病机制的一个关键特征，对人类健康产生毁灭性影响。虽然 Orientin (Ori) 对骨质疏松症的影响，特别是对 RANKL 刺激的破骨细胞生成和激活的影响仍不清楚，但已发现 Ori 具有多种生物活性，包括抗氧化和抗炎。在这项工作中，我们研究了 Ori 抑制 RANKL 诱导的破骨细胞发育的可能途径，并首次证明了它的作用。培养来自骨髓 (BMM) 的巨噬细胞，并在用 RANKL 刺激后用 Ori 进行处理。然后，对 TRAP 阳性多核细胞进行计数，并使用 F-肌动蛋白环分析来评估 Ori 对成熟破骨细胞发育的影响。此外，使用二氢乙锭 (DHE) 染色来评估 Ori 对 RANKL 诱导的活性氧 (ROS) 的影响。此外，我们还进行了蛋白质印迹和定量 RT-PCR 分析，以研究这些下调效应的可能原因。我们发现 Ori 抑制破骨细胞的产生、破骨细胞特有的基因和蛋白质表达以及 ROS 的产生。通过激活 Nrf2 和其他 ROS 清除酶，Ori 降低细胞内 ROS 水平。由于 Ori 对 RANKL 诱导的 NF-κB 的抑制，破骨细胞发育的主要转录因子 c-Fos 的表达与 NFATc1、CTSK 和 NFATc2 一起下调。与其体外抗破骨作用一致，Ori 疗法在卵巢切除 (OVX) 大鼠模型中也能够恢复骨量并改善股骨远端的微结构。总之，我们的结果表明，Ori 是一种黄酮类分子，有望治疗与破骨细胞相关的骨骼疾病，例如骨质疏松症。

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Orientin suppresses osteoclastogenesis and ameliorates ovariectomy-induced osteoporosis via suppressing ROS production

The aberrant differentiation of osteoclasts is a key feature of the pathogenesis of osteoporosis, which has a devastating impact on human health. While the effects of Orientin (Ori) on osteoporosis, particularly on RANKL-stimulated osteoclast production and activation, remain still unclear, Ori has been found to display several biological activities, including antioxidant and anti-inflammatory. In this work, we investigated the possible pathways through which Ori suppressed RANKL-induced osteoclast development and showed for the first time that it does so. The macrophages from the bone marrow (BMMs) were cultivated and then treated with Ori after being stimulated with RANKL. Then, TRAP-positive multinucleated cells were counted, and F-actin ring analysis was used to assess Ori's impact on mature osteoclast development. In addition, dihydroethidium (DHE) staining was used to evaluate the impact of Ori on RANKL-induced reactive oxygen species (ROS). In addition, we performed western blotting and quantitative RT-PCR analysis to investigate probable causes of these downregulation effects. We discovered that Ori inhibits the creation of osteoclasts, the gene and protein expressions unique to osteoclasts, and the ROS production. By activating Nrf2 and other ROS-scavenging enzymes, Ori reduces intracellular ROS levels. The expression of the main transcription factor of osteoclast development, c-Fos, was downregulated together with NFATc1, CTSK, and NFATc2, thanks to Ori's inhibition of RANKL-induced NF-κB. Consistent with its in vitro antiosteoclastogenic action, Ori therapy in the ovariectomized (OVX) rat model was also able to restore bone mass and improve microarchitecture in the distal femurs. Together, our results demonstrate that Ori is a flavonoid molecule with therapeutic promise for bone illnesses associated with osteoclasts, such as osteoporosis.

更新日期：2023-06-28

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