Synovial Fibroblasts-Derived Exosomes Overexpressing microRNA-106b Inhibits Chondrocyte Proliferation and Migration via Down-Regulation of PDK4 in Rheumatoid Arthritis

Abstract

Background: Rheumatoid arthritis (RA), an autoimmune disorder, affects people of all demographics, and exosome-derived microRNAs (miRs) have also been documented to play an important role in inflammatory disease. In view of this, our study is performed to investigate the roles of synovial fibroblasts-derived exosomes expressing miR-106b in RA via regulating PDK4. Methods: The differentially expressed genes were screened by analyzing the microarray chips related to RA. The expression of PDK4 and miR-106b were determined, and their regulatory effects on RA were evaluated. Meanwhile, exosomes derived from synovial fibroblasts (SFBs) were isolated and transferred into chondrocytes to identify the role of exosomes in RA. Furthermore, the effects of SFBs-derived exosomes overexpressing miR-106b on chondrocyte proliferation and migration were assessed using lentiviral packaged antagomir miR-106b in vivo. Results: It was found that PDK4 was down-regulated while miR-106b was up-regulated in RA. PDK4 was a target gene of miR-106b. When PDK4 was over-expressed in chondrocytes, the abilities of proliferation and migration of chondrocytes were enhanced and the RANKL/RANK/OPG system was inhibited. However, when the miR-106b was transferred into the chondrocytes by exosomes derived from SFBs, the opposite growth characteristics were identified in chondrocytes. Moreover, the investigation in vivo revealed that inhibition of miR-106b in SFBs improved the symptoms of RA in mice. Conclusion: Collectively, our study demonstrates that the SFBs-derived exosomes overexpressing miR-106b aggravates RA and affected RANKL/RANK/OPG system via down-regulation of PDK4. Funding Statement: This study was supported by grants from National Natural Science Foundation of China (no.81302576), Six Talent Peak Research Project in Jiangsu Province (no. 2015-WSN-105), the 333 Project of Jiangsu Province, Jiangsu Province Youth Medical Talent Project, Yangzhou City's Key Medical Talents Program, as well as by Jiangsu Provincial Natural Science Foundation of China (no. BK20131234). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: This study was conducted with the approval of the Ethics Committee of Affiliated Hospital of Yangzhou University. All participating patients signed written informed consent documentation prior to enrollment into the study.