MicroRNA-128a represses chondrocyte autophagy and exacerbates knee osteoarthritis by disrupting Atg12.
MicroRNA-128a represses chondrocyte autophagy and exacerbates knee osteoarthritis by disrupting Atg12.
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DOI：
10.1038/s41419-018-0994-y
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发表时间：
2018-09-11
影响因子：
9
通讯作者：
Wang FS
中科院分区：
文献类型：
--
作者：
Lian WS;Ko JY;Wu RW;Sun YC;Chen YS;Wu SL;Weng LH;Jahr H;Wang FS
软骨细胞丢失是骨关节炎（OA）的一个显著特征。自噬是维持细胞暴露于有害应激的代谢活动不可缺少的。在骨性关节炎的发展过程中，microRNA信号对软骨细胞自噬的作用尚不清楚。我们发现了终末期膝关节OA患者关节软骨细胞中自噬不良与miR-128a表达增加之间的关联，并在OA发展的大鼠前交叉韧带横断（ACLT）模型中发现了这一关联。软骨基质降解和严重的OA组织病理学在关节室内强制表达miR-128a时是明显的。关节内注射miR-128a反义寡核苷酸可稳定软骨细胞自噬，减缓aclt介导的关节组织破坏，包括软骨侵蚀、滑膜炎、骨赘形成和软骨下板损伤。在体外，miR-128信号传导通过靶向Atg12的3 ' -非翻译区，阻碍了Atg12的表达、LC3-II转化和自噬点的形成。它增加了细胞凋亡程序，降低了关节软骨细胞的软骨形成能力。组蛋白甲基转移酶EZH2的失活降低了miR-128a启动子中甲基组蛋白H3K27的富集，并上调了炎症软骨细胞中miR-128a的转录。综上所述，mir -128a诱导的Atg12缺失抑制了软骨细胞自噬，从而加剧了OA的进展。EZH2失活导致H3K27低甲基化加速miR-128a的作用。中断miR-128a信号可减弱软骨细胞功能障碍并延缓OA的发展。我们的数据为miR-128a信号如何影响软骨细胞存活和关节软骨合成代谢提供了新的见解，并强调了miR-128a靶向治疗缓解膝关节OA的潜力。
Chondrocyte loss is a prominent feature of osteoarthritis (OA). Autophagy is indispensable in maintaining the metabolic activities of cells exposed to deleterious stress. The contribution of microRNA signaling to chondrocyte autophagy in OA development remains elusive. We uncovered an association between poor autophagy and increased miR-128a expressions in articular chondrocytes of patients with end-stage knee OA and in a rat anterior cruciate ligament transection (ACLT) model for OA development. Cartilage matrix degradation and severe OA histopathology was evident upon forced miR-128a expression within the articular compartment. Intra-articular injections with miR-128a antisense oligonucleotide stabilized chondrocyte autophagy and slowed ACLT-mediated articular tissue destruction, including cartilage erosion, synovitis, osteophyte formation, and subchondral plate damage. In vitro, miR-128 signaling hindered Atg12 expression, LC3-II conversion, and autophagic puncta formation through targeting the 3′-untranslated region of Atg12. It increased apoptotic programs, diminishing cartilage formation capacity of articular chondrocytes. Inactivating histone methyltransferase EZH2 reduced methyl histone H3K27 enrichment in the miR-128a promoter and upregulated miR-128a transcription in inflamed chondrocytes. Taken together, miR-128a-induced Atg12 loss repressed chondrocyte autophagy to aggravate OA progression. EZH2 inactivation caused H3K27 hypomethylation to accelerate miR-128a actions. Interruption of miR-128a signaling attenuated chondrocyte dysfunction and delayed OA development. Our data provide new insights into how miR-128a signaling affects chondrocyte survival and articular cartilage anabolism and highlight the potential of miR-128a targeting therapy to alleviate knee OA.
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影响因子：
13.3
作者：
Haller M;Hock AK;Giampazolias E;Oberst A;Green DR;Debnath J;Ryan KM;Vousden KH;Tait SW
通讯作者：
Tait SW
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通讯作者：
Saito, Taku
影响因子：
3.7
作者：
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通讯作者：
Chen KC
影响因子：
9
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影响因子：
12.7
作者：
Chen D;Shen J;Zhao W;Wang T;Han L;Hamilton JL;Im HJ
通讯作者：
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