Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis.
Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis.
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DOI：
10.1038/s41467-021-24460-7
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发表时间：
2021-07-06
影响因子：
16.6
通讯作者：
Asahara H
中科院分区：
文献类型：
--
作者：
Ito Y;Matsuzaki T;Ayabe F;Mokuda S;Kurimoto R;Matsushima T;Tabata Y;Inotsume M;Tsutsumi H;Liu L;Shinohara M;Tanaka Y;Nakamichi R;Nishida K;Lotz MK;Asahara H
骨关节炎（OA）是最常见的与年龄相关的关节疾病，是由细胞外基质合成和降解失衡引起的。在这里，我们发现microRNA-455（miR-455）的两条链，-5p和-3p，被软骨分化和功能所必需的转录因子Sox 9上调。miR-455- 5 p和-3p在来自正常关节软骨的人软骨细胞和小鼠原代软骨细胞中高度表达。我们产生了miR-455敲除小鼠，并发现在6个月大时观察到类似OA的软骨变性和软骨变性相关基因的表达升高。利用基于细胞的miRNA靶点筛选系统，我们鉴定了低氧诱导因子-2 α（HIF-2α），一种软骨稳态的分解代谢因子，作为miR-455- 5 p和-3p的直接靶点。此外，miR-455- 5 p和-3p的过表达在小鼠OA模型中保护软骨变性，证明了它们的潜在治疗价值。此外，在6个月大的miR-455敲除软骨中，HIF-2α的敲低挽救了软骨变性相关基因的表达升高。这些数据表明，一个miRNA的两条链靶向相同的基因来调节关节软骨的稳态。骨关节炎是由细胞外基质合成和降解之间的失衡引起的。在这里，作者表明microRNA-455的两条链，-5p和-3p，靶向HIF 2 α并调节软骨稳态，并表明这些miRNA的过表达对小鼠骨关节炎具有保护作用。
Osteoarthritis (OA), the most common aging-related joint disease, is caused by an imbalance between extracellular matrix synthesis and degradation. Here, we discover that both strands of microRNA-455 (miR-455), -5p and -3p, are up-regulated by Sox9, an essential transcription factor for cartilage differentiation and function. Both miR-455-5p and -3p are highly expressed in human chondrocytes from normal articular cartilage and in mouse primary chondrocytes. We generate miR-455 knockout mice, and find that cartilage degeneration mimicking OA and elevated expression of cartilage degeneration-related genes are observed at 6-months-old. Using a cell-based miRNA target screening system, we identify hypoxia-inducible factor-2α (HIF-2α), a catabolic factor for cartilage homeostasis, as a direct target of both miR-455-5p and -3p. In addition, overexpression of both miR-455-5p and -3p protect cartilage degeneration in a mouse OA model, demonstrating their potential therapeutic value. Furthermore, knockdown of HIF-2α in 6-month-old miR-455 knockout cartilage rescues the elevated expression of cartilage degeneration-related genes. These data demonstrate that both strands of a miRNA target the same gene to regulate articular cartilage homeostasis. Osteoarthritis is caused by an imbalance between extracellular matrix synthesis and degradation. Here, the authors show that both strands of microRNA-455, -5p and -3p, target HIF2α and regulate cartilage homeostasis, and show that overexpression of these miRNAs is protective against osteoarthritis in mice.
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影响因子：
56.9
作者：
Lagos-Quintana, M;Rauhut, R;Tuschl, T
通讯作者：
Tuschl, T
影响因子：
--
作者：
Grogan, Shawn P.;Olee, Tsaiwei;Hiraoka, Koji;Lotz, Martin K.
通讯作者：
Lotz, Martin K.
影响因子：
5
作者：
Belmont PJ;Chen WJ;Thuerauf DJ;Glembotski CC
通讯作者：
Glembotski CC
影响因子：
5
作者：
Haag, Jochen;Gebhard, Pia M.;Aigner, Thomas
通讯作者：
Aigner, Thomas
影响因子：
15.9
作者：
GOLDRING, MB;BIRKHEAD, J;KRANE, SM
通讯作者：
KRANE, SM