DUSP6 expression is associated with osteoporosis through the regulation of osteoclast differentiation via ERK2/Smad2 signaling.
DUSP6 expression is associated with osteoporosis through the regulation of osteoclast differentiation via ERK2/Smad2 signaling.
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DUSP6 表达通过 ERK2/Smad2 信号传导调节破骨细胞分化与骨质疏松症相关
DOI：
10.1038/s41419-021-04110-y
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发表时间：
2021-09-02
影响因子：
9
通讯作者：
Sun X
中科院分区：
文献类型：
--
作者：
Zhang B;Yuan P;Xu G;Chen Z;Li Z;Ye H;Wang J;Shi P;Sun X
骨质疏松相关的骨折，如股骨颈和椎骨骨折，在老年人中很常见，导致残疾率和医疗保健费用增加。因此，阐明破骨细胞相关性骨质疏松症的发生机制，寻找有效的防治方法具有重要意义。在这项研究中，基因表达谱分析和实时聚合酶链反应显示，DUSP 6表达在人类和小鼠骨质疏松症病例中受到抑制。体外实验证实，DUSP 6过表达阻止破骨细胞生成，而通过小干扰RNA或化学抑制剂（E/Z）-BCI抑制DUSP 6具有相反的效果。（E/Z）-BCl通过增强破骨细胞生成显著加速体内骨丢失过程。生物信息学分析和体外实验表明，miR-181 a是DUSP 6的上游调控因子。此外，miR-181 a通过DUSP 6正向诱导破骨细胞分化，负向调节破骨细胞凋亡。此外，还发现ERK 2和SMAD 2的下游信号也参与了这一过程。ERK 2缺陷骨髓源性巨噬细胞的评估证实了ERK 2信号传导在DUSP 6介导的破骨细胞生成中的作用。此外，免疫沉淀试验证实，DUSP 6直接修饰SMAD 2的磷酸化状态和随后的NFATC 1的核转运，以调节破骨细胞分化。总之，这项研究首次证明了miRNA-181 a/DUSP 6通过ERK 2和SMAD 2信号通路在骨质疏松症进展中的作用。因此，DUSP 6可能代表未来治疗破骨细胞相关疾病的新靶点。
Osteoporosis-related fractures, such as femoral neck and vertebral fractures, are common in aged people, resulting in increased disability rate and health-care costs. Thus, it is of great importance to clarify the mechanism of osteoclast-related osteoporosis and find effective ways to avoid its complication. In this study, gene expression profile analysis and real-time polymerase chain reaction revealed that DUSP6 expression was suppressed in human and mice osteoporosis cases. In vitro experiments confirmed that DUSP6 overexpression prevented osteoclastogenesis, whereas inhibition of DUSP6 by small interference RNA or with a chemical inhibitor, (E/Z)-BCI, had the opposite effect. (E/Z)-BCl significantly accelerated the bone loss process in vivo by enhancing osteoclastogenesis. Bioinformatics analyses and in vitro experiments indicated that miR-181a was an upstream regulator of DUSP6. Moreover, miR-181a positively induced the differentiation and negatively regulated the apoptosis of osteoclasts via DUSP6. Furthermore, downstream signals by ERK2 and SMAD2 were also found to be involved in this process. Evaluation of ERK2-deficiency bone marrow-derived macrophages confirmed the role of ERK2 signaling in the DUSP6-mediated osteoclastogenesis. Additionally, immunoprecipitation assays confirmed that DUSP6 directly modified the phosphorylation status of SMAD2 and the subsequent nuclear transportation of NFATC1 to regulate osteoclast differentiation. Altogether, this study demonstrated for the first time the role of miRNA-181a/DUSP6 in the progression of osteoporosis via the ERK2 and SMAD2 signaling pathway. Hence, DUSP6 may represent a novel target for the treatment of osteoclast-related diseases in the future.
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影响因子：
--
作者：
Hari SB;Merritt EA;Maly DJ
通讯作者：
Maly DJ
影响因子：
16.6
作者：
Kagoya Y;Nakatsugawa M;Saso K;Guo T;Anczurowski M;Wang CH;Butler MO;Arrowsmith CH;Hirano N
通讯作者：
Hirano N
影响因子：
82.9
作者：
Dankbar, Berno;Fennen, Michelle;Pap, Thomas
通讯作者：
Pap, Thomas
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DOI：
10.1016/j.bbadis.2019.06.010
发表时间：
2019-09-01
影响因子：
6.2
作者：
Sun, Xuewu;Huang, Hai;Shi, Peihua
通讯作者：
Shi, Peihua
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影响因子：
4.8
作者：
Shao, Bingyi;Liao, Li;Jin, Yan
通讯作者：
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