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Synovial fibroblast-derived exosomal microRNA-106b suppresses chondrocyte proliferation and migration in rheumatoid arthritis via down-regulation of PDK4

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Abstract

Fibroblast-derived exosomes have been reported to transfer microRNAs to recipient cells, where they regulate target gene expression, which is of interest for understanding the basic biology of inflammation, tissue homeostasis, and development of therapeutic approaches. Initial microarray-based analysis carried out in this study identified the rheumatoid arthritis (RA)–related differentially expressed gene pyruvate dehydrogenase kinase 4 (PDK4). Subsequently, the upstream regulatory microRNA-106b (miR-106b) of PDK4 was predicted with bioinformatic analyses. A collagen-induced arthritis (CIA)-induced mouse model was established, and exosomes were isolated from synovial fibroblasts (SFs) and transferred into chondrocytes to identify the role of exosomes in rheumatoid arthritis (RA). We found that PDK4 was poorly expressed in RA cartilage tissues and chondrocytes, while miR-106b was highly expressed in RA SFs and SF-derived exosomes. Notably, PDK4 was confirmed as a target gene of miR-106b. Over-expression of PDK4 promoted the proliferation and migration abilities of chondrocytes and inhibited their apoptosis as well as affected the receptor activator of nuclear factor kappa B ligand (RANKL)/RANK/osteoprotegerin (OPG) system. Meanwhile, miR-106b was delivered from SFs to chondrocytes through exosomes, which suppressed chondrocyte proliferation and migration and accelerated apoptosis as well as affected the RANKL/RANK/OPG system via down-regulation of PDK4. Furthermore, in vivo results validated that miR-106b inhibition could relieve CIA-induced RA. Taken together, SF-derived exosomal miR-106b stimulates RA initiation by targeting PDK4, indicating a physiologically validated potential approach for the prevention and treatment of RA.

Key messages

  • PDK4 is decreased in chondrocytes of RA, while miR-106b is increased in SFBs.

  • PDK4 promotes proliferation and migration of chondrocytes.

  • miR-106b could target 3′UTR of PDK4 gene.

  • SFB-exosomal miR-106b inhibits proliferation and migration of chondrocytes.

  • Inhibition of miR-106b attenuates RA progression in a CIA mouse model.

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Acknowledgments

We acknowledge and appreciate our colleagues for their valuable efforts and comments on this paper.

Funding

This study was supported by grants from the National Natural Science Foundation of China (No. 81302576 and No. 81402936), Six Talent Peak Research Project in Jiangsu Province (No. 2015-WSN-105), the 333 Project of Jiangsu Province, Jiangsu Province Youth Medical Talent Project (No. QNRC2016348), Key Talents of Science and Education in Yangzhou City in 13th Five-Year (No. ZDRC201881), and Jiangsu Provincial Natural Science Foundation of China (No. BK20131234).

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  1. Dan Liu, Yuxuan Fang and Yujun Rao contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou University, Yangzhou, 225000, People’s Republic of China

    Dan Liu

  2. Department of Rheumatology and Immunology, Affiliated Hospital of Yangzhou University, Yangzhou University, No. 368, Hanjiang Middle Road, Yangzhou, 225000, Jiangsu Province, People’s Republic of China

    Yuxuan Fang, Yujun Rao, Wei Tan, Wei Zhou, Xia Wu, Chunwang Zhang & Guoqing Li

  3. Clinical Medical College, Dalian Medical University, Dalian, 116044, People’s Republic of China

    Xia Wu & Chunwang Zhang

  4. Medical College of Yangzhou University, Yangzhou, 225000, People’s Republic of China

    Yu Zhang & Yanqing Liu

  5. Department of Physiology, School of Medicine, Showa University, Tokyo, 142-8555, Japan

    Masataka Sunagawa & Tadashi Hisamitsu

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  1. Dan Liu
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Contributions

DL, YXF, YJR, WT, WZ, and XW designed the study. DL, YXF, CWZ, YZ, YQL, and MS collated the data, carried out data analyses, and produced the initial draft of the manuscript. YJR, TH, and GQL contributed in drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Guoqing Li.

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The authors declare that they have no conflict of interest.

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This study was conducted with the approval of the Ethics Committee of the Affiliated Hospital of Yangzhou University. All participating patients signed written informed consent documentation prior to enrollment into the study. The animal experiment protocol was approved by the medical ethics committee of the Affiliated Hospital of Yangzhou University and strictly adhered to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health to minimize the usage, suffering, and discomfort to experimental animals.

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Liu, D., Fang, Y., Rao, Y. et al. Synovial fibroblast-derived exosomal microRNA-106b suppresses chondrocyte proliferation and migration in rheumatoid arthritis via down-regulation of PDK4. J Mol Med 98, 409–423 (2020). https://doi.org/10.1007/s00109-020-01882-2

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