Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A.
Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A.
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源自过表达 miR-92a-3p 的人间充质干细胞的外泌体通过靶向 WNT5A 增强软骨形成并抑制软骨降解。
DOI：
10.1186/s13287-018-1004-0
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发表时间：
2018-09-26
影响因子：
7.5
通讯作者：
Kang Y
中科院分区：
文献类型：
--
作者：
Mao G;Zhang Z;Hu S;Zhang Z;Chang Z;Huang Z;Liao W;Kang Y
已知WNT 5A参与骨关节炎的发病机制。本研究探讨了外泌体miR-92 a-3 p和WNT 5A在软骨发生和软骨退变中的分子机制。在软骨形成的人间充质干细胞（MSC）模型和正常和OA原代人软骨细胞（PHCs）中体外评估外来体miR-92 a-3 p表达。MSC和PHCs分别用来源于MSC-miR-92 a-3 p的外泌体（MSC-miR-92 a-3 p-Exos）或其反义抑制剂（MSC-anti-miR-92 a-3 p-Exos）处理。利用小干扰RNA（siRNA）和荧光素酶报告基因分析揭示外泌体miR-92 a-3 p和WNT 5A在软骨形成中的分子作用。使用番红-O和Fast绿色染色和免疫组织化学染色测量外来体在体内的保护作用。外泌体miR-92 a-3 p表达在MSC软骨形成外泌体中升高，而与正常软骨相比，其在OA软骨细胞分泌的外泌体中显著降低。MSC-miR-92 a-3 p-Exos处理分别促进MSC和PHCs中的软骨增殖和基质基因表达。相反，用MSC-抗-miR-92 a-3 p-Exos治疗通过增强WNT 5A的表达抑制软骨形成分化并减少软骨基质合成。荧光素酶报告基因分析表明，miR-92 a-3 p抑制了含有3 '-UTR的报告基因构建体的活性，并抑制了MSC和PHCs中WNT 5A的表达。MSC-miR-92 a-3 p-Exos抑制OA小鼠模型中的软骨降解。我们的研究结果表明，外泌体miR-92 a-3 p通过直接靶向WNT 5A调节软骨发育和稳态。这表明外泌体miR-92 a-3 p可以作为Wnt抑制剂，并表现出作为疾病修饰骨关节炎药物的潜力。本文的在线版本（10.1186/s13287-018-1004-0）包含补充材料，可供授权用户使用。
WNT5A is known to be involved in the pathogenesis of osteoarthritis. This study investigated the molecular mechanism of exosomal miR-92a-3p and WNT5A in chondrogenesis and cartilage degeneration. Exosomal miR-92a-3p expression was assessed in vitro in a human mesenchymal stem cell (MSC) model of chondrogenesis and in normal and OA primary human chondrocytes (PHCs). MSCs and PHCs were treated with exosomes derived from MSC-miR-92a-3p (MSC-miR-92a-3p-Exos) or its antisense inhibitor (MSC-anti-miR-92a-3p-Exos), respectively. Small interfering RNAs (siRNAs) and luciferase reporter assay were used to reveal the molecular role of exosomal miR-92a-3p and WNT5A in chondrogenesis. The protective effect of exosomes in vivo was measured using Safranin-O and Fast Green staining and immunohistochemical staining. Exosomal miR-92a-3p expression was elevated in the MSC chondrogenic exosome, while it was significantly reduced in the OA chondrocyte-secreted exosome compared with normal cartilage. Treatment with MSC-miR-92a-3p-Exos promoted cartilage proliferation and matrix genes expression in MSCs and PHCs, respectively. In contrast, treatment with MSC-anti-miR-92a-3p-Exos repressed chondrogenic differentiation and reduced cartilage matrix synthesis by enhancing the expression of WNT5A. Luciferase reporter assay demonstrated that miR-92a-3p suppressed the activity of a reporter construct containing the 3’-UTR and inhibited WNT5A expression in both MSCs and PHCs. MSC-miR-92a-3p-Exos inhibit cartilage degradation in the OA mice model. Our results suggest that exosomal miR-92a-3p regulates cartilage development and homeostasis by directly targeting WNT5A. This indicates that exosomal miR-92a-3p may act as a Wnt inhibitor and exhibits potential as a disease-modifying osteoarthritis drug. The online version of this article (10.1186/s13287-018-1004-0) contains supplementary material, which is available to authorized users.
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影响因子：
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