Decreased miR-214-3p activates NF-κB pathway and aggravates osteoarthritis progression.
Decreased miR-214-3p activates NF-κB pathway and aggravates osteoarthritis progression.
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miR-214-3p 减少激活 NF-κB 通路并加剧骨关节炎进展
DOI：
10.1016/j.ebiom.2021.103283
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发表时间：
2021-03
期刊：
影响因子：
11.1
通讯作者：
Ding C
中科院分区：
文献类型：
--
作者：
Cao Y;Tang S;Nie X;Zhou Z;Ruan G;Han W;Zhu Z;Ding C
骨关节炎（OA）是一种全关节损伤和功能障碍的疾病，是全球致残的主要原因。透明软骨细胞外基质（ECM）的进行性丧失被认为是其标志，但其确切的发病机制有待进一步阐明。MicroRNA（miRNA）有助于OA病理，并可能有助于识别新的生物标志物和治疗OA。在这里，我们发现miR-214-3p是OA的重要调节因子。采用qRT-PCR和原位杂交检测miR-214-3p的表达水平。通过western blotting、免疫荧光、qRT-PCR和荧光素酶检测来评估miR-214-3p在OA中的功能，以及miR-214-3p与其下游mRNA靶点（IKBKB）的相互作用。采用小鼠模型研究miR-214-3p在OA中的体内功能和机制。在我们的研究中，我们发现miR-214-3p在炎症软骨细胞和OA软骨中下调的同时，调节软骨中的ECM代谢和细胞凋亡。机械上，miR-214-3p的保护作用下调IKK-β表达，导致NF-κB信号通路功能障碍。此外，在小鼠关节内关节内注射miR-214-3p阿塔戈米尔会引发自发性软骨丢失，而miRNA-214-3p阿塔戈米尔则会减轻实验小鼠模型中的OA。降低miR-214-3p激活NF-κB信号通路，通过靶向IKKβ加重OA的发展，提示miR-214-3p可能是OA的一种新的治疗靶点。本研究由国家自然科学基金（81,773,532,81,974,342）资助。
Osteoarthritis (OA), a disease with whole-joint damage and dysfunction, is the leading cause of disability worldwide. The progressive loss of hyaline cartilage extracellular matrix (ECM) is considered as its hallmark, but its exact pathogenesis needs to be further clarified. MicroRNA(miRNA) contributes to OA pathology and may help to identify novel biomarkers and therapies against OA. Here we identified miR-214–3p as an important regulator of OA. qRT-PCR and in situ hybridization were used to detect the expression level of miR-214–3p. The function of miR-214–3p in OA, as well as the interaction between miR-214–3p and its downstream mRNA target (IKBKB), was evaluated by western blotting, immunofluorescence, qRT-PCR and luciferase assay. Mice models were introduced to examine the function and mechanism of miR-214–3p in OA in vivo. In our study, we found that miR-214–3p, while being down-regulated in inflamed chondrocytes and OA cartilage, regulated ECM metabolism and cell apoptosis in the cartilage. Mechanically, the protective effect of miR-214–3p downregulated the IKK-β expression and led to the dysfunction of NF-κB signaling pathway. Furthermore, intra-articular injection of miR-214–3p antagomir in mice joints triggered spontaneous cartilage loss while miRNA-214–3p agomir alleviated OA in the experimental mouse models. Decreased miR-214–3p activates the NF-κB signaling pathway and aggravates OA development through targeting IKKβ, suggesting miR-214–3p may be a novel therapeutic target for OA. This study was financially supported by grants from the National Natural Science Foundation of China (81,773,532, 81,974,342).
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