Downregulation of miR-221-3p contributes to IL-1β-induced cartilage degradation by directly targeting the SDF1/CXCR4 signaling pathway
| Autor: | Shaosong Sun, Xin Zheng, Yong Pang, Dong-Ya Li, Feng-Chao Zhao, Sheng-Cheng Yao, Kai-Jin Guo |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Receptors CXCR4 DNA Complementary Interleukin-1beta Down-Regulation Chondrocyte Cell Line Extracellular matrix 03 medical and health sciences Chondrocytes Downregulation and upregulation Osteoarthritis Drug Discovery microRNA Gene expression medicine Humans Cells Cultured Genetics (clinical) Aged Gene knockdown Reverse Transcriptase Polymerase Chain Reaction Sequence Analysis RNA Chemistry Transfection Middle Aged Chemokine CXCL12 Extracellular Matrix Cell biology MicroRNAs Cartilage 030104 developmental biology medicine.anatomical_structure Real-time polymerase chain reaction Molecular Medicine Female Signal Transduction |
| Zdroj: | Journal of Molecular Medicine. 95:615-627 |
| ISSN: | 1432-1440 0946-2716 |
| DOI: | 10.1007/s00109-017-1516-6 |
| Popis: | Osteoarthritis (OA) is characterized by degradation of chondrocyte extracellular matrix (ECM). Accumulating evidence suggests that microRNAs (miRNAs) are associated with OA, but little is known of their function in chondrocyte ECM degradation. The objective of this study was to investigate the expression and function of miRNAs in OA. miRNA expression profile was determined in OA cartilage tissues and controls, employing Solexa sequencing and reverse transcription quantitative PCR (RT-qPCR). According to a modified Mankin scale, cartilage degradation was evaluated. Functional analysis of the miRNAs on chondrocyte ECM degradation was performed after miRNA transfection and IL-1β treatment. Luciferase reporter assays and western blotting were employed to determine miRNA targets. Expression of miR-221-3p was downregulated in OA cartilage tissues, which was significantly correlated with a modified Mankin scale. Through gain-of-function and loss-of-function studies, miR-221-3p was shown to significantly affect matrix synthesis gene expression and chondrocyte proliferation and apoptosis. Using SW1353 and C28I2 cells, SDF1 was identified as a target of miR-221-3p. SDF1 overexpression resulted in increased expression of catabolic genes such as MMP-13 and ADAMTS-5 in response to IL-1β, but these effects were moderated by miR-221-3p. SDF1 treatment antagonized this effect, while knockdown of SDF1 by shSDF1 induced inhibitory effects on the expression of CXCR4 and its main target genes, similar to miR-221-3p. The results indicate that upregulation of miR-221-3p could prevent IL-1β-induced ECM degradation in chondrocytes. Targeting the SDF1/CXCR4 signaling pathway may be used as a therapeutic approach for OA. miR-221-3p is downregulated in human cartilage tissues. miR-221-3p levels are associated with cartilage degeneration grade. miR-221-3p upregulation prevents IL-1β-induced ECM degradation in chondrocytes. Protection of ECM degradation by miR-223-3p occurs via SDF1/CXCR4 signaling. miR-221-3p is identified as a novel potential therapeutic target for osteoarthritis. KEY MESSAGES: miR-221-3p is downregulated in human cartilage tissues. miR-221-3p levels are associated with cartilage degeneration grade. miR-221-3p upregulation prevents IL-1β-induced ECM degradation in chondrocytes. Protection of ECM degradation by miR-223-3p occurs via SDF1/CXCR4 signaling. miR-221-3p is identified as a novel potential therapeutic target for osteoarthritis. |
| Databáze: | OpenAIRE |
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