miR-214-3p 表达下调激活 NF-κB 通路并加重骨关节炎进展。
Decreased miR-214-3p activates NF-κB pathway and aggravates osteoarthritis progression.
机构信息
Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Rheumatology and Immunology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Centre of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
出版信息
EBioMedicine. 2021 Mar;65:103283. doi: 10.1016/j.ebiom.2021.103283. Epub 2021 Mar 11.
BACKGROUND
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.
METHODS
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.
FINDINGS
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.
INTERPRETATION
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.
FUNDING
This study was financially supported by grants from the National Natural Science Foundation of China (81,773,532, 81,974,342).
背景
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，但确切的发病机制仍需进一步阐明。微小 RNA（miRNA）有助于 OA 病理学，并可能有助于确定针对 OA 的新型生物标志物和治疗方法。在这里，我们将 miR-214-3p 鉴定为 OA 的重要调节因子。
方法
使用 qRT-PCR 和原位杂交检测 miR-214-3p 的表达水平。通过 Western blot、免疫荧光、qRT-PCR 和荧光素酶测定评估 miR-214-3p 在 OA 中的功能以及 miR-214-3p 与其下游 mRNA 靶标（IKBKB）之间的相互作用。引入小鼠模型以体内研究 miR-214-3p 在 OA 中的功能和机制。
发现
在我们的研究中，我们发现 miR-214-3p 在炎症性软骨细胞和 OA 软骨中下调，调节软骨中的 ECM 代谢和细胞凋亡。在机制上，miR-214-3p 的下调通过抑制 IKK-β 的表达并导致 NF-κB 信号通路功能障碍来发挥保护作用。此外，向小鼠关节内注射 miR-214-3p 反义寡核苷酸会引发自发性软骨丢失，而 miRNA-214-3p 激动剂则可减轻实验性小鼠模型中的 OA。
解释
miR-214-3p 的减少激活了 NF-κB 信号通路，并通过靶向 IKKβ 加重了 OA 的发展，表明 miR-214-3p 可能是 OA 的一种新的治疗靶点。
资金
本研究得到了国家自然科学基金（81,773,532，81,974,342）的资助。
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