MicroRNA-21-5p as a novel therapeutic target for osteoarthritis
| Autor: | Xiao-Bo Wang, Feng-Chao Zhao, Dong-Ya Li, Yong Pang, Chen Yeshuai, Xin Zheng, Jinlong Tang, Linhong Yi, Kai-Jin Guo, Zheng-Ya Zhu |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
030203 arthritis & rheumatology
0301 basic medicine business.industry FGF18 Transfection Osteoarthritis medicine.disease Chondrocyte Blot 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Rheumatology Conditional gene knockout microRNA medicine Cancer research Gene silencing Pharmacology (medical) business |
| Zdroj: | Rheumatology. 58:1485-1497 |
| ISSN: | 1462-0332 1462-0324 |
| DOI: | 10.1093/rheumatology/kez102 |
| Popis: | Objective Growing evidence indicates that microRNAs (miRNA) play a critical role in the pathogenesis of OA, and overexpressing or silencing miRNA expression in OA models can contribute to the development of miRNA-based therapeutics. The objective of this study was to determine whether intra-articular injection of miRNA can inhibit OA progression. Methods The miRNA expression profile was determined in OA cartilage tissues and controls. Functional analysis of the miRNAs on extracellular matrix degradation was performed after miRNA mimic or inhibitor transfection. Luciferase reporter assays and western blotting were employed to determine miRNA targets. To investigate the functional mechanism of miR-21-5p in OA development, miR-21-5pfl/flCol2a1-CreER and wild-type mice were subject to surgical destabilization of the medial meniscus. Therapeutically, wild-type mice undergoing surgical destabilization of the medial meniscus were treated with intra-articular injection of agomir- and antagomir-21-5p. Results We found that expression of miR-21-5p was significantly up-regulated in OA cartilage tissues. The articular cartilage degradation of miR-21-5p conditional knockout mice was significantly alleviated compared with that of wild-type mice in spontaneous and destabilization of the medial meniscus models. Through gain-of-function and loss-of-function studies, miR-21-5p was shown to significantly affect matrix synthesis genes expression, and chondrocyte proliferation and apoptosis. Further, fibroblast growth factor 18 (FGF18) was identified as a target of miR-21-5p. Intra-articular injection of antagomir-21-5p significantly attenuated the severity of experimental OA. Clinically, FGF18 expression level was correlated with miR-21-5p expression and a modified Mankin scale. Conclusion Our findings reveal a miRNA functional pathway important for OA development, highlighting miRNA-21-5p silencing as an attractive therapeutic regimen in future clinical trials involving patients with OA. |
| Databáze: | OpenAIRE |
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