A Long Non-Coding RNA, GAS5, Plays a Critical Role in the Regulation of miR-21 During Osteoarthritis
A Long Non-Coding RNA, GAS5, Plays a Critical Role in the Regulation of miR-21 During Osteoarthritis
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DOI：
10.1002/jor.22718
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发表时间：
2014-12-01
影响因子：
2.8
通讯作者：
Jin, Eun-Jung
中科院分区：
文献类型：
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作者：
Song, Jinsoo;Ahn, Chihyun;Jin, Eun-Jung
已知生长抑制特异性5 （Growth Arrest-Specific 5, GAS5）负性调节细胞存活，并在几种癌症中异常表达。GAS5对骨关节炎（OA）的影响尚未确定。为了解决这个问题，我们从全膝关节置换术（TKR）患者软骨的相对正常（非OA）和清晰OA区域（OA）中分离关节软骨细胞，并对正常软骨进行活检。我们发现，与非OA软骨细胞和正常软骨细胞相比，OA软骨细胞中GAS5表达上调。过表达GAS5可使MMP-2、MMP-3、MMP-9、MMP-13、ADAMTS-4等多种MMPs的表达水平升高；刺激细胞凋亡;抑制自噬反应。此外，我们随后确定了miR-21在OA发病过程中是GAS5的调节因子。OA患者miR-21的表达水平明显降低，GAS5的异位表达能够抑制miR-21的诱导。与GAS5实验一致，miR-21的引入刺激了软骨细胞的凋亡，抑制了包括LC-3B在内的自噬复合物的表达水平。在体内，我们发现将miR-21引入OA小鼠软骨中可显著刺激软骨破坏。综上所述，这些结果表明GAS5作为miR-21的负调节因子，从而调节细胞存活，从而参与OA的发病机制。(c) 2014年骨科研究会。Wiley期刊公司出版。[J]中华口腔医学杂志，2014,32(2):628- 635。
Growth Arrest-Specific 5 (GAS5) is known to negatively regulate cell survival and is aberrantly expressed in several cancers. The influence of GAS5 on osteoarthritis (OA) has not been determined. To address this, articular chondrocytes were isolated from relatively normal (Non-OA) and clear OA regions (OA) of cartilage in total knee replacement (TKR) patients and biopsied normal cartilage. We found that GAS5 was up-regulated in OA chondrocytes compared with Non-OA and normal chondrocytes. The over-expression of GAS5 increased the expression levels of several MMPs, such as MMP-2, MMP-3, MMP-9, MMP-13, and ADAMTS-4; stimulated apoptosis; and suppressed autophagic responses. Furthermore, we subsequently identified miR-21 as a regulator of GAS5 during OA pathogenesis. The expression level of miR-21 was significantly reduced in OA patients, and the ectopic expression of GAS5 is capable of suppressing miR-21 induction. Consistent with GAS5 experiments, the introduction of miR-21 stimulated the apoptosis of chondrocytes and inhibited the expression levels of autophagic complexes, including LC-3B. In vivo, we found that the introduction of miR-21 into the cartilage of OA mice significantly stimulated cartilage destruction. Together, these results show that GAS5 contributes to the pathogenesis of OA by acting as a negative regulator of miR-21 and thereby regulating cell survival. (c) 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1628-1635, 2014.