miR-31 controls osteoclast formation and bone resorption by targeting RhoA.
miR-31 controls osteoclast formation and bone resorption by targeting RhoA.
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DOI：
10.1186/ar4282
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发表时间：
2013
影响因子：
4.9
通讯作者：
Kohsaka H
中科院分区：
文献类型：
--
作者：
Mizoguchi F;Murakami Y;Saito T;Miyasaka N;Kohsaka H
破骨细胞活性增加是类风湿性关节炎中骨丢失和关节破坏的原因。对于破骨细胞的发育和骨吸收活性，细胞骨架组织必须得到适当的调节。microRNAs（miRNAs）是一种内源性小分子非编码RNA，可抑制靶基因的表达。本研究旨在鉴定控制破骨细胞的关键miRNAs。用miRNA芯片分析骨髓源性巨噬细胞（BMM）在有或无核因子κB受体激活因子配体（RANKL）刺激下的miRNA表达。为了检测特异性miRNA在破骨细胞形成、骨吸收活性和肌动蛋白环形成中的作用，用miRNA逆转录病毒转导BMM。为了证实miR-31抑制对破骨细胞生成的抑制作用是否通过靶向RhoA介导，在RhoA抑制剂胞外酶C3存在下分析破骨细胞形成。miR-31被鉴定为RANKL刺激下破骨细胞发育过程中高度上调的miRNA之一。通过特异性抑制剂抑制miR-31可抑制RANKL诱导的破骨细胞形成和骨吸收。对破骨细胞的鬼笔环肽染色显示，miR-31抑制严重损害了细胞周边的肌动蛋白环形成，取而代之的是观察到成簇的小环状podosomes。在这些破骨细胞中，尽管破骨细胞生成受损，但miR-31抑制仍上调了miR-31靶基因之一RhoA的表达。用RhoA抑制剂外切酶C3治疗，挽救了因miR-31抑制而受损的破骨细胞生成。miR-31通过调节RhoA的表达来控制破骨细胞中的细胞骨架组织以获得最佳的骨吸收活性。
Increased activity of osteoclasts is responsible for bone loss and joint destruction in rheumatoid arthritis. For osteoclast development and bone resorption activity, cytoskeletal organization must be properly regulated. MicroRNAs (miRNAs) are endogenous small noncoding RNAs that suppress expression of their target genes. This study was conducted to identify crucial miRNAs to control osteoclasts. miRNA expression in the bone marrow-derived macrophages (BMM) with or without receptor activator of nuclear factor κB ligand (RANKL) stimulation was analyzed by miRNA array. To examine the role of specific miRNAs in osteoclast formation, bone resorption activity and actin ring formation, the BMM were retrovirally transduced with miRNA antagomirs. To confirm whether the suppressive effects on osteoclastogenesis by miR-31 inhibition were mediated by targeting RhoA, osteoclast formation was analyzed in the presence of the RhoA inhibitor, exoenzyme C3. miR-31 was identified as one of the highly upregulated miRNAs during osteoclast development under RANKL stimulation. Inhibition of miR-31 by specific antagomirs suppressed the RANKL-induced formation of osteoclasts and bone resorption. Phalloidin staining of osteoclasts revealed that actin ring formation at the cell periphery was severely impaired by miR-31 inhibition, and clusters of small ringed podosomes were observed instead. In these osteoclasts, expression of RhoA, one of the miR-31 target genes, was upregulated by miR-31 inhibition in spite of the impaired osteoclastogenesis. Treatment with the RhoA inhibitor, exoenzyme C3, rescued the osteoclastogenesis impaired by miR-31 inhibition. miR-31 controls cytoskeleton organization in osteoclasts for optimal bone resorption activity by regulating the expression of RhoA.
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影响因子：
3.3
作者：
Kurokawa, K;Matsuda, M
通讯作者：
Matsuda, M
影响因子：
4.8
作者：
Chellaiah, MA;Soga, N;Hruska, KA
通讯作者：
Hruska, KA
影响因子：
20.3
作者：
Sugatani, Toshifumi;Vacher, Jean;Hruska, Keith A.
通讯作者：
Hruska, Keith A.
影响因子：
4
作者：
Mizoguchi, Fumitaka;Izu, Yayoi;Noda, Masaki
通讯作者：
Noda, Masaki
影响因子：
64.5
作者：
Valastyan S;Reinhardt F;Benaich N;Calogrias D;Szász AM;Wang ZC;Brock JE;Richardson AL;Weinberg RA
通讯作者：
Weinberg RA