艾瑞宁作为一种NFATc1抑制剂，可预防乳腺癌诱导的破骨细胞生成和骨质破坏。
Erianin serves as an NFATc1 inhibitor to prevent breast cancer-induced osteoclastogenesis and bone destruction.
作者信息
Zheng Jiehuang, He Weili, Chen Yan, Li Lihong, Liang Qinghe, Dai Wenqi, Li Ruopeng, Chen Fengsheng, Chen Ziye, Tan Yanhui, Li Xiaojuan
机构信息
Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, Innovation Program of Drug Research on Inflammatory and Immune Diseases, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Department of Breast Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510630, China.
出版信息
J Adv Res. 2025 Mar;69:399-411. doi: 10.1016/j.jare.2024.03.021. Epub 2024 Mar 30.
INTRODUCTION
Breast cancer-related bone metastasis can lead to skeletal-related events (SREs), which decrease patient quality of life. Inhibition of osteoclastogenesis is a key treatment for SREs; however, the availability of clinical drugs remains limited, and all existing ones disrupt physiological bone formation, while exhibiting no effect on patient survival time.
OBJECTIVES
This study aimed to identify a novel osteoclast inhibitor for the treatment of breast cancer-induced SREs.
METHODS
The MDA-MB-231 breast cancer cell-induced bone loss model was used to investigate the therapeutic effects of erianin in vivo. Then, we evaluated the inhibitory effects of erianin on osteoclastogenesis and signalling in bone marrow-derived macrophages (BMMs) induced by conditioned medium from MDA-MB-231 breast cancer cells (231 CM) and receptor activator of nuclear factor-κB ligand (RANKL) in vitro. Next, a Cellular Thermal Shift Assay and siRNA-mediate knockdown were performed, to investigate the target of erianin during osteoclast formation. The effects of erianin on human osteoclastogenesis were evaluated using CD14 monocytes obtained from patients with breast cancer.
RESULTS
Erianin effectively improved breast cancer cells-induced bone destruction at doses of 2 and 20 mg/kg/day in vivo, while suppressing osteoclastogenesis and the upregulation of SRC-NFATc1, INTEGRIN β3-MMP9 signals induced by 231 CM and RANKL in vitro. Furthermore, erianin interacted with NFATc1 but not SRC, and Nfatc1 knockdown eliminated the inhibitory effects of erianin on osteoclastogenesis. Notably, lower expression of NFATc1 positively correlated with longer survival in patients with cancer and a high risk of bone metastasis. We further revealed that 62.5-250 nM erianin suppresses NFATc1 and excessive osteoclastogenesis in CD14 monocytes from patients with breast cancer.
CONCLUSION
Erianin acts as an NFATc1 inhibitor that attenuates breast cancer-induced osteoclastogenesis and bone destruction.
引言
乳腺癌相关骨转移可导致骨相关事件（SREs），降低患者生活质量。抑制破骨细胞生成是治疗SREs的关键；然而，临床可用药物仍然有限，且所有现有药物都会干扰生理性骨形成，同时对患者生存时间无影响。
目的
本研究旨在鉴定一种用于治疗乳腺癌诱导的SREs的新型破骨细胞抑制剂。
方法
使用MDA-MB-231乳腺癌细胞诱导的骨质流失模型在体内研究毛兰素的治疗效果。然后，我们在体外评估了毛兰素对由MDA-MB-231乳腺癌细胞条件培养基（231 CM）和核因子κB受体活化因子配体（RANKL）诱导的骨髓来源巨噬细胞（BMMs）中破骨细胞生成和信号传导的抑制作用。接下来，进行细胞热位移分析和小干扰RNA介导的敲低，以研究毛兰素在破骨细胞形成过程中的作用靶点。使用从乳腺癌患者获得的CD14单核细胞评估毛兰素对人破骨细胞生成的影响。
结果
毛兰素在体内以2和20mg/kg/天的剂量有效改善乳腺癌细胞诱导的骨破坏，同时在体外抑制破骨细胞生成以及由231 CM和RANKL诱导的SRC-NFATc1、整合素β3-MMP9信号的上调。此外，毛兰素与NFATc1相互作用，但不与SRC相互作用，并且Nfatc1敲低消除了毛兰素对破骨细胞生成的抑制作用。值得注意的是，NFATc1的低表达与癌症患者和骨转移高风险患者的较长生存期呈正相关。我们进一步发现，62.5-250 nM毛兰素可抑制乳腺癌患者CD14单核细胞中的NFATc1和过度破骨细胞生成。
结论
毛兰素作为一种NFATc1抑制剂，可减轻乳腺癌诱导的破骨细胞生成和骨破坏。
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