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Downregulation of miR-221-3p contributes to IL-1β-induced cartilage degradation by directly targeting the SDF1/CXCR4 signaling pathway

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Abstract

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.

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Acknowledgements

We thank all the donors enrolled in the present study.

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Authors and Affiliations

  1. Department of Orthopaedics, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road West, Xuzhou, 221006, China

    Xin Zheng, Feng-chao Zhao, Yong Pang, Dong-ya Li, Sheng-cheng Yao, Shao-song Sun & Kai-jin Guo

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  1. Xin Zheng
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  2. Feng-chao Zhao
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  3. Yong Pang
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  4. Dong-ya Li
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Corresponding author

Correspondence to Kai-jin Guo.

Ethics declarations

Informed consent from each patient was obtained, and this work was approved by the ethics committee of our institution.

Conflict of interest

The authors declare no conflict of interest related to this study.

Funding

This work has received support from the National Natural Science Foundation of China (81672184), the Key Program of Science and Technique Development Foundation in Jiangsu Province (BE2015627, BE2016642), the Research project of Jiangsu Provincial Health Department (H201528), the China Postdoctoral Science Foundation funded project (2016M591929), and the Social Development Project of Xuzhou Municipal Science and Technology Bureau (KC15SH067).

Additional information

Xin Zheng and Feng-chao Zhao contributed equally to this work.

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Zheng, X., Zhao, Fc., Pang, Y. et al. Downregulation of miR-221-3p contributes to IL-1β-induced cartilage degradation by directly targeting the SDF1/CXCR4 signaling pathway. J Mol Med 95, 615–627 (2017). https://doi.org/10.1007/s00109-017-1516-6

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  • DOI: https://doi.org/10.1007/s00109-017-1516-6

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