Department of Dental Anesthesiology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan.
Department of Biochemistry and Molecular Biology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan.
Int J Mol Sci. 2024 Jul 12;25(14):7651. doi: 10.3390/ijms25147651.
Drug repositioning is a method for exploring new effects of existing drugs, the safety and pharmacokinetics of which have been confirmed in humans. Here, we demonstrate the potential drug repositioning of midazolam (MDZ), which is used for intravenous sedation, as an inhibitor of inflammatory bone resorption. We cultured a mouse macrophage-like cell line with or without MDZ and evaluated its effects on the induction of differentiation of these cells into osteoclasts. For in vivo investigations, we administered lipopolysaccharide (LPS) together with MDZ (LPS+MDZ) to the parietal region of mice and evaluated the results based on the percentage of bone resorption and calvaria volume. Furthermore, we examined the effects of MDZ on the production of reactive oxygen species (ROS) in cells and on its signaling pathway. MDZ inhibited osteoclast differentiation and bone resorption activity. In animal studies, the LPS+MDZ group showed a decreasing trend associated with the rate of bone resorption. In addition, the bone matrix volume in the LPS+MDZ group was slightly higher than in the LPS only group. MDZ inhibited osteoclast differentiation by decreasing ROS production and thereby negatively regulating the p38 mitogen-activated protein kinase pathway. Thus, we propose that MDZ could potentially be used for treating inflammatory bone resorption, for example, in periodontal disease.
药物重定位是一种探索现有药物新作用的方法，这些药物的安全性和药代动力学已经在人体中得到证实。在这里，我们证明了咪达唑仑（MDZ）作为一种炎症性骨吸收抑制剂的潜在药物重定位，MDZ 用于静脉镇静。我们培养了一种具有或不具有 MDZ 的小鼠巨噬细胞样细胞系，并评估了其对这些细胞分化为破骨细胞的诱导作用。为了进行体内研究，我们将 LPS 和 MDZ（LPS+MDZ）一起施用于小鼠顶骨区域，并根据骨吸收百分比和颅骨体积评估结果。此外，我们还研究了 MDZ 对细胞内活性氧（ROS）产生及其信号通路的影响。MDZ 抑制破骨细胞分化和骨吸收活性。在动物研究中，LPS+MDZ 组显示出与骨吸收率相关的下降趋势。此外，LPS+MDZ 组的骨基质体积略高于 LPS 组。MDZ 通过减少 ROS 产生来抑制破骨细胞分化，从而负调控 p38 丝裂原活化蛋白激酶途径。因此，我们提出 MDZ 可能可用于治疗炎症性骨吸收，例如牙周病。
