Obacunone targets macrophage migration inhibitory factor (MIF) to impede osteoclastogenesis and alleviate ovariectomy-induced bone loss.
Obacunone targets macrophage migration inhibitory factor (MIF) to impede osteoclastogenesis and alleviate ovariectomy-induced bone loss.
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Obacunone 以巨噬细胞迁移抑制因子 (MIF) 为靶点，阻止破骨细胞生成并减轻卵巢切除术引起的骨质流失。
DOI：
10.1016/j.jare.2023.01.003
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发表时间：
2023-11
影响因子：
10.7
通讯作者：
Chen, Kai
中科院分区：
文献类型：
--
作者：
He, Jianbo;Zheng, Lin;Li, Xiaojuan;Huang, Furong;Hu, Sitao;Chen, Lei;Jiang, Manya;Lin, Xianfeng;Jiang, Haibo;Zeng, Yifan;Ye, Tianshen;Lin, Dingkun;Liu, Qian;Xu, Jiake;Chen, Kai
关键词：
Obacunone（OB）靶向巨噬细胞移动抑制因子（MIF），以阻止破骨细胞生成和减轻骨质疏松症。Obacunone（OB）在体外能有效抑制破骨细胞的形成和功能。OB减弱RANKL诱导的破骨细胞分化信号通路。巨噬细胞移动抑制因子（Macrophage migration inhibitor factor，MIF）是OB的分子靶点。OB通过阻碍破骨细胞的过度活动来缓解雌激素缺乏引起的骨丢失。OB可作为骨质疏松症的替代治疗候选者。骨质疏松症是最常见的骨疾病，其中过度活跃的破骨细胞在发病过程中起主导作用。靶向过度活跃的破骨细胞是目前的主要治疗策略。然而，对目前一线治疗的长期疗效和副作用的担忧仍然存在。仍然需要替代治疗剂。Obacunone（OB）是一种具有广谱生物活性的小分子，特别是抗氧化和抗炎作用。本研究旨在探讨OB对骨质疏松症的治疗潜力及其作用机制。通过体外破骨细胞形成和骨吸收实验检测OB的抑制作用，并通过卵巢切除诱导的骨质疏松临床前模型研究OB的治疗作用。为了进一步研究其机制，我们采用mRNA测序和分析来研究下游通路的变化。预测了OB的分子靶点，并进行了计算机对接分析。通过表面等离子体共振（SPR）分析和蛋白质印迹分析验证配体-靶结合。结果表明，OB在体外抑制破骨细胞的形成及其吸收功能。在机制上，OB与巨噬细胞移动抑制因子（MIF）相互作用，从而减弱核因子κ B（NF-κB）配体（RANKL）诱导的信号通路，包括活性氧（ROS）、NF-κB通路和促分裂原活化蛋白激酶（MAPK）。这些作用最终导致破骨细胞生成的主转录因子、活化T细胞核因子1（NFATc 1）及其下游破骨细胞特异性蛋白的表达水平降低。此外，我们的数据显示，OB减轻雌激素缺乏引起的骨质疏松症，通过靶向MIF，从而抑制体内破骨细胞过度活跃。这些结果共同暗示OB可能代表作为破骨细胞引起的骨疾病，如骨质疏松症的治疗候选者。
Obacunone (OB) targets macrophage migration inhibitory factor (MIF) to impede osteoclastogenesis and alleviate osteoporosis. Obacunone (OB) effectively inhibits osteoclast formation and function in vitro. OB attenuates RANKL-induced osteoclast differentiation signaling pathways. Macrophage migration inhibitory factor (MIF) is identified as the molecular target of OB. OB alleviates estrogen deficiency-induced bone loss by impeding excessive osteoclast activity. OB may serve as an alternative therapeutic candidate for osteoporosis. Osteoporosis is the most common bone disorder where the hyperactive osteoclasts represent the leading role during the pathogenesis. Targeting hyperactive osteoclasts is currently the primary therapeutic strategy. However, concerns about the long-term efficacy and side effects of current frontline treatments persist. Alternative therapeutic agents are still needed. Obacunone (OB) is a small molecule with a broad spectrum of biological activities, particularly antioxidant and anti-inflammatory effects. This study aims to examine OB’s therapeutic potential on osteoporosis and explore the rudimentary mechanisms. Osteoclast formation and osteoclastic resorption assays were carried out to examine OB’s inhibitory effects in vitro, followed by the in-vivo studies of OB’s therapeutic effects on ovariectomy-induced osteoporotic preclinical model. To further study the underlying mechanisms, mRNA sequencing and analysis were used to investigate the changes of downstream pathways. The molecular targets of OB were predicted, and in-silico docking analysis was performed. Ligand-target binding was verified by surface plasmon resonance (SPR) assay and Western Blotting assay. The results indicated that OB suppressed the formation of osteoclast and its resorptive function in vitro. Mechanistically, OB interacts with macrophage migration inhibitory factor (MIF) which attenuates receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL)-induced signaling pathways, including reactive oxygen species (ROS), NF-κB pathway, and mitogen-activated protein kinases (MAPKs). These effects eventually caused the diminished expression level of the master transcriptional factor of osteoclastogenesis, nuclear factor of activated T cells 1 (NFATc1), and its downstream osteoclast-specific proteins. Furthermore, our data revealed that OB alleviated estrogen deficiency-induced osteoporosis by targeting MIF and thus inhibiting hyperactive osteoclasts in vivo. These results together implicated that OB may represent as a therapeutic candidate for bone disorders caused by osteoclasts, such as osteoporosis.
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影响因子：
5.6
作者：
Chen, Kai;Yuan, Yu;Xu, Jiake
通讯作者：
Xu, Jiake
DOI：
10.1007/978-1-4939-7000-1_26
发表时间：
2017
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Burley SK;Berman HM;Kleywegt GJ;Markley JL;Nakamura H;Velankar S
通讯作者：
Velankar S
影响因子：
15.3
作者：
Asagiri, M;Sato, K;Takayanagi, H
通讯作者：
Takayanagi, H
Obacunone 引起 MKP-1 持续表达，从而使 p38 MAPK 失活，从而通过细胞内 MIF 抑制促炎介质
影响因子：
4
作者：
Gao, Yuan;Hou, Rui;Qi, Yun
通讯作者：
Qi, Yun
影响因子：
4.2
作者：
Cotzomi-Ortega, Israel;Rosas-Cruz, Arely;Maycotte, Paola
通讯作者：
Maycotte, Paola