MicroRNA-218 Negatively Regulates Osteoclastogenic Differentiation by Repressing the Nuclear Factor-kappaB Signaling Pathway and Targeting Tumor Necrosis Factor Receptor 1.
MicroRNA-218 Negatively Regulates Osteoclastogenic Differentiation by Repressing the Nuclear Factor-kappaB Signaling Pathway and Targeting Tumor Necrosis Factor Receptor 1.
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MicroRNA-218 通过抑制核因子-kappaB 信号通路和靶向肿瘤坏死因子受体 1 负向调节破骨细胞分化。
DOI：
10.1159/000491740
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Zhang Hongxiu
中科院分区：
文献类型：
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作者：
Wang Weiwei;Yang Lei;Zhang Dan;Gao Chao;Wu Jie;Zhu Yunxia;Zhang Hongxiu
背景/目的绝经后骨质疏松症是一种与雌激素缺乏相关的常见疾病，导致骨丢失和骨组织改变。由此产生的骨脆性和骨折风险的增加对老年人的健康和生活质量产生了严重的不利影响，使其成为一个重要的健康问题。MicroRNA-218(miR-218)与骨质疏松症的发生发展密切相关。本研究探讨了miR-218在破骨细胞形成中的调控机制。方法与正常细胞比较，研究miR-218对RAW 264.7细胞向破骨细胞分化的影响。接下来，将miR-218模拟物或抑制剂导入RAW 264.7细胞，研究miR-218在破骨细胞分化中的作用。抗酒石酸酸性磷酸酶(TRAP)染色检测破骨细胞分化程度。用生物信息学分析和荧光素酶报告基因分析鉴定和验证miR-218靶基因。结果在RAW 264.7细胞分化为破骨细胞后，miR-218表达下调。MiR-218的过表达抑制了破骨细胞的分化，而miR-218的低表达促进了破骨细胞的分化，这表现为破骨细胞特异性基因的表达增加和TRAP染色。生物信息学分析和荧光素酶报告基因分析表明，肿瘤坏死因子受体1是肿瘤坏死因子的细胞膜受体(肿瘤坏死因子受体是核因子-κB的激活剂)，是miR-218的直接靶点。结论miR-218通过靶向肿瘤坏死因子受体1抑制核因子-κB信号，负向调节破骨细胞分化，提示靶向miR-218可能是治疗绝经后骨质疏松症的一种途径。
Background/AimsPostmenopausal osteoporosis is a common disease associated with estrogen deficiency leading to bone loss and bone tissue changes. The resultant bone fragility and increased risk of fracture has serious adverse effects on health and quality of life of the elderly, making it an important health issue. MicroRNA-218 (miR-218) is closely related to the development of osteoporosis. In this study, we investigated the regulatory mechanisms of miR-218 in osteoclastogenesis.MethodsWe investigated miR-218 levels on differentiation of RAW 264.7 cells into osteoclasts compared with normal cells. Next, RAW 264.7 cells were transfected with miR-218 mimics or inhibitors to study the role of miR-218 in osteoclastogenic differentiation. Tartrate-resistant acid phosphatase (TRAP) staining was performed to determine osteoclastogenic differentiation. Bioinformatics analysis and luciferase reporter assay were used to identify and validate miR-218 target genes.ResultsmiR-218 was downregulated following RAW 264.7 cell differentiation into osteoclasts. miR-218 overexpression attenuated osteoclast differentiation, whereas low miR-218 expression promoted it as demonstrated by increased expression of osteoclast-specific genes and TRAP staining. Bioinformatics analysis and the luciferase reporter assay showed that tumor necrosis factor receptor 1 (TNFR1), a cell membrane receptor of TNF (TNF is an activator of nuclear factor-κB [NF-κB]), is a direct target of miR-218.ConclusionsOur findings indicate that miR-218 regulates osteoclastogenic differentiation negatively by repressing NF-κB signaling by targeting TNFR1, suggesting that targeting miR-218 may be a therapeutic approach in postmenopausal osteoporosis.