Bone protection by inhibition of microRNA-182.
Bone protection by inhibition of microRNA-182.
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DOI：
10.1038/s41467-018-06446-0
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发表时间：
2018-10-05
影响因子：
16.6
通讯作者：
Zhao B
中科院分区：
文献类型：
--
作者：
Inoue K;Deng Z;Chen Y;Giannopoulou E;Xu R;Gong S;Greenblatt MB;Mangala LS;Lopez-Berestein G;Kirsch DG;Sood AK;Zhao L;Zhao B
靶向microRNAs最近显示出显著的治疗前景；然而，在骨质疏松症和类风湿性关节炎（RA）等骨溶解性疾病的治疗方面，这方面的进展尚不充分。在这里，我们发现miR-182在骨稳态和疾病中是一个关键的破骨细胞生成调节因子。在卵巢切除引起的骨质疏松症和炎症性关节炎疾病模型中，miR-182的骨髓特异性缺失保护小鼠免受过度破骨细胞发生和骨吸收。用miR-182抑制剂对这些疾病进行药物治疗可完全抑制病理性骨侵蚀。在机制上，我们发现蛋白激酶双链rna依赖（PKR）是一个新的和必要的miR-182靶点，它是一种新的破骨细胞生成抑制剂，通过调节内源性干扰素(IFN)-β介导的自分泌反馈回路。miR-182、PKR和IFN-β的表达水平在RA中发生改变，并与RA单核细胞的破骨能力显著相关。我们的研究结果揭示了一个先前未被认识的由miR-182- pkr - ifn -β轴介导的破骨细胞发生调节网络，并强调了miR-182抑制在骨保护中的治疗意义。破骨细胞在许多退行性骨病中介导骨破坏。在这里，作者表明miR-182通过PKR和ifn - β信号调节破骨细胞生成，与类风湿关节炎相关，并且在骨质疏松症或炎症性关节炎小鼠模型中，miR-182的消融或抑制对骨侵蚀具有保护作用。
Targeting microRNAs recently shows significant therapeutic promise; however, such progress is underdeveloped in treatment of skeletal diseases with osteolysis, such as osteoporosis and rheumatoid arthritis (RA). Here, we identified miR-182 as a key osteoclastogenic regulator in bone homeostasis and diseases. Myeloid-specific deletion of miR-182 protects mice against excessive osteoclastogenesis and bone resorption in disease models of ovariectomy-induced osteoporosis and inflammatory arthritis. Pharmacological treatment of these diseases with miR-182 inhibitors completely suppresses pathologic bone erosion. Mechanistically, we identify protein kinase double-stranded RNA-dependent (PKR) as a new and essential miR-182 target that is a novel inhibitor of osteoclastogenesis via regulation of the endogenous interferon (IFN)-β-mediated autocrine feedback loop. The expression levels of miR-182, PKR, and IFN-β are altered in RA and are significantly correlated with the osteoclastogenic capacity of RA monocytes. Our findings reveal a previously unrecognized regulatory network mediated by miR-182-PKR-IFN-β axis in osteoclastogenesis, and highlight the therapeutic implications of miR-182 inhibition in osteoprotection. Osteoclasts mediate bone disruption in a number of degenerative bone diseases. Here, the authors show that miR-182 regulates osteoclastogenesis via PKR and IFN-beta signaling, is correlated with rheumatoid arthritis, and that its ablation or inhibition is protective against bone erosion in mouse models of osteoporosis or inflammatory arthritis.
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DOI：
10.1016/j.omtn.2017.06.005
发表时间：
2017-09-15
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Chakraborty C;Sharma AR;Sharma G;Doss CGP;Lee SS
通讯作者：
Lee SS
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
3.7
作者：
Haller O;Kochs G;Weber F
通讯作者：
Weber F
影响因子：
15.3
作者：
Kim, N;Kadono, Y;Choi, Y
通讯作者：
Choi, Y
影响因子：
4.8
作者：
Abraham, N;Stojdl, DF;Bell, JC
通讯作者：
Bell, JC