CircNFIX regulates chondrogenesis and cartilage homeostasis by targeting the miR758-3p/KDM6A axis.
CircNFIX regulates chondrogenesis and cartilage homeostasis by targeting the miR758-3p/KDM6A axis.
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CircNFIX 通过靶向 miR758-3p/KDM6A 轴调节软骨形成和软骨稳态
DOI：
10.1111/cpr.13302
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发表时间：
2022-11
影响因子：
8.5
通讯作者：
中科院分区：
文献类型：
--
作者：
骨关节炎（OA）是一种导致关节软骨进行性破坏的退行性疾病；然而，病因尚未阐明。据报道，环状rna （circRNAs）参与软骨变性和OA的发展。在本研究中，我们发现circNFIX调节软骨形成和软骨稳态。通过微阵列分析，研究了人脂肪驱动干细胞（hADSCs）软骨分化过程中circRNA的表达。使用定量逆转录-聚合酶链反应和原位杂交检测CircNFIX的表达。进行了功能增益和功能损失分析，以验证circNFIX在软骨稳态中的作用。通过RNA pull - down、Argonaute2 - RNA免疫沉淀和荧光素酶报告基因检测来评估circNFIX、miR758‐3p和KDM6A之间的相互作用。CircNFIX在hADSC软骨形成的早期和中期表达上调，而在晚期表达下调。CircNFIX抑制可减弱hADSC软骨形成。CircNFIX在OA样品中显著下调，CircNFIX过表达保护软骨细胞降解，并减轻内侧半月板OA模型不稳定的OA进展。在机制上，circNFIX作为miR758‐3p的海绵，通过靶向miR‐758‐3p/KDM6A轴，在软骨形成和软骨细胞变性中发挥作用。我们的研究结果揭示了circNFIX在软骨形成和软骨稳态中的关键作用，这可能为OA治疗提供潜在的治疗策略。circNFIX对人脂肪驱动干细胞（hADSCs）软骨形成和软骨稳态影响的示意图。本研究结果显示circNFIX能够促进hascs的软骨分化，维持软骨稳态。在机制上，circNFIX作为miR758‐3p的海绵，通过靶向miR‐758‐3p/KDM6A轴调节SOX9的甲基化水平，从而介导hascs的软骨分化和软骨稳态。circNFIX/miR‐758‐3p/KDM6A轴可能作为软骨退变和OA治疗的有效治疗靶点。
Osteoarthritis (OA) is a degenerative disease causing the progressive destruction of articular cartilage; however, the aetiology has not yet been elucidated. Circular RNAs (circRNAs) are reportedly involved in cartilage degeneration and OA development. In the present study, we identified that circNFIX regulates chondrogenesis and cartilage homeostasis. Microarray analysis was performed to explore circRNA expression during the chondrogenic differentiation of human adipose‐drived stem cells (hADSCs). CircNFIX expression was determined using quantitative reverse transcription‐polymerase chain reaction and in situ hybridization. Gain‐ and loss‐of‐function assays were performed to validate the role of circNFIX in cartilage homeostasis. RNA pull‐down, Argonaute2‐RNA immunoprecipitation and luciferase reporter assays were performed to evaluate the interactions among circNFIX, miR758‐3p and KDM6A. CircNFIX expression was upregulated in the early and middle stages, whereas downregulated in the late stage of hADSC chondrogenesis. CircNFIX inhibition attenuated hADSC chondrogenesis. CircNFIX was remarkably downregulated in OA samples, circNFIX overexpression protected against chondrocyte degradation and alleviated OA progression in the destabilization of the medial meniscus OA model. Mechanistically, circNFIX acted as a sponge of miR758‐3p and played a role in the chondrogenesis and chondrocyte degeneration by targeting the miR‐758‐3p/KDM6A axis. Our results revealed a key role of circNFIX in chondrogenesis and cartilage homeostasis, which may provide a potential therapeutic strategy for OA treatment. Schematic illustration of the effects of circNFIX on human adipose‐drived stem cells (hADSCs) chondrogenesis and cartilage homeostasis. The results of this study revealed that circNFIX can promote the chondrogenic differentiation of hADSCs and maintain cartilage homeostasis. Mechanistically, circNFIX acted as a sponge of miR758‐3p regulated the methylation level of SOX9 by targeting the miR‐758‐3p/KDM6A axis, thereby mediating the chondrogenic differentiation of hADSCs and cartilage homeostasis. The circNFIX/miR‐758‐3p/KDM6A axis may serve as an effective therapeutic target for cartilage degeneration and OA treatment.
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