Cryptotanshinone Protects Cartilage against Developing Osteoarthritis through the miR-106a-5p/GLIS3 Axis.
Cryptotanshinone Protects Cartilage against Developing Osteoarthritis through the miR-106a-5p/GLIS3 Axis.
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隐丹参酮通过 miR-106a-5p/GLIS3 轴保护软骨免受骨关节炎的发展
DOI：
10.1016/j.omtn.2018.02.001
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发表时间：
2018-06-01
期刊：
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Ji Q;Qi D;Xu X;Xu Y;Goodman SB;Kang L;Song Q;Fan Z;Maloney WJ;Wang Y
隐丹参酮（CTS）已成为骨关节炎（OA）的抗炎药。然而，其有效治疗OA的分子机制仍不甚清楚。MicroRNAs （miRNAs）在维持软骨稳态中起着至关重要的调节作用。为了研究CTS是否通过调节miRNA来防止OA的发生，我们使用微阵列分析检测了CTS介导的潜在miRNA分子。我们发现CTS显著促进miR-106a-5p在软骨细胞中的表达。通过前交叉韧带横断建立的OA小鼠模型，我们发现关节内注射miR-106a-5p agomir可减轻OA。此外，miR-106a-5p通过直接靶向3 '非翻译区抑制glii -similar 3 （GLIS3）的产生。CTS通过将配对盒（PAX）转录因子家族的成员PAX5招募到miR-106a-5p启动子，促进了miR-106a-5p的表达。PAX5的抑制模拟了miR-106a-5p的作用，并消除了CTS调节miR-106a-5p表达的能力。在OA患者中，miR-106-5p下调，同时伴有PAX5下调和GLIS3上调。总的来说，这些数据强调PAX5/miR-106a-5p/GLIS3轴在ccs介导的OA软骨保护中作为一种新的多效调节因子，这表明miR-106a-5p和PAX5的激活以及GLIS3的抑制可能对OA患者的治疗策略有用且有吸引力。
Cryptotanshinone (CTS) has emerged as an anti-inflammatory agent in osteoarthritis (OA). However, the molecular mechanism underlying its potent therapeutic effect on OA remains largely unknown. MicroRNAs (miRNAs) act as crucial regulators in maintaining cartilage homeostasis. To investigate whether CTS protects against developing OA through regulation of miRNAs, we examined the potential CTS-mediated miRNA molecules using microarray analysis. We found that CTS significantly promoted miR-106a-5p expression in chondrocytes. Using the OA mouse model created by anterior cruciate ligament transection, we revealed that intra-articular injection of miR-106a-5p agomir attenuated OA. In addition, miR-106a-5p inhibited GLI-similar 3 (GLIS3) production by directly targeting the 3′ untranslated region. CTS promoted miR-106a-5p expression through recruitment of a member of the paired box (PAX) family of transcription factors, PAX5, to the miR-106a-5p promoter. Inhibition of PAX5 mimicked the effect of miR-106a-5p and abolished the CTS ability to regulate miR-106a-5p expression. In OA patients, miR-106-5p is downregulated which is accompanied by downregulation of PAX5 and upregulation of GLIS3. Collectively, these data highlight that the PAX5/miR-106a-5p/GLIS3 axis acts as a novel pleiotropic regulator in CTS-mediated OA cartilage protection, suggesting that miR-106a-5p and PAX5 activation and GLIS3 inhibition might be useful and attractive for therapeutic strategies to treat OA patients.
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