Top

Arthritis Research & Therapy

Published in:

01-12-2021 | Osteoarthrosis | Research article

Exosomal circ-BRWD1 contributes to osteoarthritis development through the modulation of miR-1277/TRAF6 axis

Authors: Zhenye Guo, Huan Wang, Feng Zhao, Min Liu, Feida Wang, Mingming Kang, Weifu He, Zhi Lv

Published in: Arthritis Research & Therapy | Issue 1/2021

Abstract

Background

Circular RNAs (circRNAs) can act as vital players in osteoarthritis (OA). However, the roles of circRNAs in OA remain obscure. Herein, we explored the roles of exosomal circRNA bromodomain and WD repeat domain containing 1(circ-BRWD1) in OA pathology.

Methods

In vitro model of OA was constructed by treating CHON-001 cells with interleukin-1β (IL-1β). Quantitative real-time polymerase chain reaction (qRT-PCR) assay was used for circ-BRWD1, BRWD, miR-1277, and TNF receptor-associated factor 6 (TRAF6) levels. RNase R assay was conducted for the feature of circ-BRWD1. Transmission electron microscopy (TEM) was employed to analyze the morphology of exosomes. Western blot assay was performed for protein levels. Cell Counting Kit-8 (CCK-8) assay, flow cytometry analysis, and 5-Ethynyl-2′-deoxyuridine (EDU) assay were adopted for cell viability, apoptosis, and proliferation, respectively. Enzyme-linked immunosorbent assay (ELISA) was carried out for the concentrations of interleukin-6 (IL-6) and interleukin-8 (IL-8). Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were used to analyze the interaction between miR-1277 and circ-BRWD1 or TRAF6.

Results

Circ-BRWD1 was increased in OA cartilage tissues, IL-1β-treated CHON-001 cells, and the exosomes derived from IL-1β-treated CHON-001 cells. Exosome treatment elevated circ-BRWD1 level, while exosome blocker reduced circ-BRWD1 level in IL-1β-treated CHON-001 cells. Silencing of circ-BRWD1 promoted cell viability and proliferation and repressed apoptosis, inflammation, and extracellular matrix (ECM) degradation in IL-1β-stimulated CHON-001 cells. For mechanism analysis, circ-BRWD1 could serve as the sponge for miR-1277 to positively regulate TRAF6 expression. Moreover, miR-1277 inhibition ameliorated the effects of circ-BRWD1 knockdown on IL-1β-mediated CHON-001 cell damage. Additionally, miR-1277 overexpression relieved IL-1β-induced CHON-001 cell injury, while TRAF6 elevation restored the impact.

Conclusion

Exosomal circ-BRWD1 promoted IL-1β-induced CHON-001 cell progression by regulating miR-1277/TRAF6 axis.

van der Kraan PM. Osteoarthritis year 2012 in review: biology. Osteoarthr Cartil. 2012;20(12):1447–50. https://doi.org/10.1016/j.joca.2012.07.010.CrossRef

Glyn-Jones S, Palmer AJ, Agricola R, Price AJ, Vincent TL, Weinans H, et al. Osteoarthritis. Lancet. 2015;386(9991):376–87. https://doi.org/10.1016/S0140-6736(14)60802-3.CrossRefPubMed

Dreier R. Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Res Ther. 2010;12(5):216. https://doi.org/10.1186/ar3117.CrossRefPubMedPubMedCentral

Rahmati M, Nalesso G, Mobasheri A, Mozafari M. Aging and osteoarthritis: central role of the extracellular matrix. Ageing Res Rev. 2017;40:20–30.CrossRef

Honvo G, Reginster JY, Rabenda V, Geerinck A, Mkinsi O, Charles A, et al. Safety of symptomatic slow-acting drugs for osteoarthritis: outcomes of a systematic review and meta-analysis. Drugs Aging. 2019;36(Suppl 1):65–99. https://doi.org/10.1007/s40266-019-00662-z.CrossRefPubMedPubMedCentral

Mathiessen A, Conaghan PG. Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis Res Ther. 2017;19(1):18. https://doi.org/10.1186/s13075-017-1229-9.CrossRefPubMedPubMedCentral

Patop IL, Kadener S. circRNAs in cancer. Curr Opin Genet Dev. 2018;48:121–7.CrossRef

Zhou R, Wu Y, Wang W, Su W, Liu Y, Wang Y, et al. Circular RNAs (circRNAs) in cancer. Cancer Lett. 2018;425:134–42.CrossRef

Wu Y, Zhang Y, Zhang Y, Wang JJ. CircRNA hsa_circ_0005105 upregulates NAMPT expression and promotes chondrocyte extracellular matrix degradation by sponging miR-26a. Cell Biol Int. 2017;41(12):1283–9. https://doi.org/10.1002/cbin.10761.CrossRefPubMed

10.

Li BF, Zhang Y, Xiao J, Wang F, Li M, Guo XZ, et al. Hsa_circ_0045714 regulates chondrocyte proliferation, apoptosis and extracellular matrix synthesis by promoting the expression of miR-193b target gene IGF1R. Hum Cell. 2017;30(4):311–8. https://doi.org/10.1007/s13577-017-0177-7.CrossRefPubMed

11.

Li Z, Yuan B, Pei Z, Zhang K, Ding Z, Zhu S, et al. Circ_0136474 and MMP-13 suppressed cell proliferation by competitive binding to miR-127-5p in osteoarthritis. J Cell Mol Med. 2019;23(10):6554–64. https://doi.org/10.1111/jcmm.14400.CrossRefPubMedPubMedCentral

12.

Sun Z, Shi K, Yang S, Liu J, Zhou Q, Wang G, et al. Effect of exosomal miRNA on cancer biology and clinical applications. Mol Cancer. 2018;17(1):147. https://doi.org/10.1186/s12943-018-0897-7.CrossRefPubMedPubMedCentral

13.

Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl). 2013;91(4):431–7. https://doi.org/10.1007/s00109-013-1020-6.CrossRef

14.

Nana-Sinkam SP, Croce CM. MicroRNA regulation of tumorigenesis, cancer progression and interpatient heterogeneity: towards clinical use. Genome Biol. 2014;15(9):445. https://doi.org/10.1186/s13059-014-0445-8.CrossRefPubMedPubMedCentral

15.

Yan S, Wang M, Zhao J, Zhang H, Zhou C, Jin L, et al. MicroRNA-34a affects chondrocyte apoptosis and proliferation by targeting the SIRT1/p53 signaling pathway during the pathogenesis of osteoarthritis. Int J Mol Med. 2016;38(1):201–9. https://doi.org/10.3892/ijmm.2016.2618.CrossRefPubMedPubMedCentral

16.

Dai L, Zhang X, Hu X, Zhou C, Ao Y. Silencing of microRNA-101 prevents IL-1beta-induced extracellular matrix degradation in chondrocytes. Arthritis Res Ther. 2012;14(6):R268. https://doi.org/10.1186/ar4114.CrossRefPubMedPubMedCentral

17.

Wang T, Liu Y, Wang Y, Huang X, Zhao W, Zhao Z. Long non-coding RNA XIST promotes extracellular matrix degradation by functioning as a competing endogenous RNA of miR-1277-5p in osteoarthritis. Int J Mol Med. 2019;44(2):630–42. https://doi.org/10.3892/ijmm.2019.4240.CrossRefPubMedPubMedCentral

18.

West C, McDermott MF. Effects of microRNA-146a on the proliferation and apoptosis of human osteochondrocytes by targeting TRAF6 through the NF- kappaB signalling pathway. Biosci Rep. 2017;37(4):BSR20170180.CrossRef

19.

Jung MK, Mun JY. Sample preparation and imaging of exosomes by transmission electron microscopy. J Vis Exp. 2018;131:56482.

20.

Zeng L, Wang W, Rong X-F, Zhong Y, Jia P, Zhou G-Q, et al. Chondroprotective effects and multi-target mechanisms of Icariin in IL-1 beta-induced human SW 1353 chondrosarcoma cells and a rat osteoarthritis model. Int Immunopharmacol. 2014;18(1):175–81. https://doi.org/10.1016/j.intimp.2013.11.021.CrossRefPubMed

21.

Daheshia M, Yao JQ. The interleukin 1beta pathway in the pathogenesis of osteoarthritis. J Rheumatol. 2008;35(12):2306–12. https://doi.org/10.3899/jrheum.080346.CrossRefPubMed

22.

Liu D, Kang H, Gao M, Jin L, Zhang F, Chen D, et al. Exosome-transmitted circ_MMP2 promotes hepatocellular carcinoma metastasis by upregulating MMP2. Mol Oncol. 2020;14(6):1365–80. https://doi.org/10.1002/1878-0261.12637.CrossRefPubMedPubMedCentral

23.

Li T, Sun X, Chen L. Exosome circ_0044516 promotes prostate cancer cell proliferation and metastasis as a potential biomarker. J Cell Biochem. 2020;121(3):2118–26.

24.

Zhu H, Hu Y, Wang C, Zhang X, He D. CircGCN1L1 promotes synoviocyte proliferation and chondrocyte apoptosis by targeting miR-330-3p and TNF-alpha in TMJ osteoarthritis. Cell Death Dis. 2020;11(4):284. https://doi.org/10.1038/s41419-020-2447-7.CrossRefPubMedPubMedCentral

25.

Sofat N. Analysing the role of endogenous matrix molecules in the development of osteoarthritis. Int J Exp Pathol. 2009;90(5):463–79. https://doi.org/10.1111/j.1365-2613.2009.00676.x.CrossRefPubMedPubMedCentral

26.

Nagase H, Kashiwagi M. Aggrecanases and cartilage matrix degradation. Arthritis Res Ther. 2003;5(2):94–103. https://doi.org/10.1186/ar630.CrossRefPubMedPubMedCentral

27.

Huang S, Wa Q, Pan J, Peng X, Ren D, Huang Y, et al. Downregulation of miR-141-3p promotes bone metastasis via activating NF-kappaB signaling in prostate cancer. J Exp Clin Cancer Res. 2017;36(1):173. https://doi.org/10.1186/s13046-017-0645-7.CrossRefPubMedPubMedCentral

28.

Rosenberger CM, Podyminogin RL, Diercks AH, Treuting PM, Peschon JJ, Rodriguez D, et al. miR-144 attenuates the host response to influenza virus by targeting the TRAF6-IRF7 signaling axis. PLoS Pathog. 2017;13(4):e1006305.CrossRef

29.

He Q, Qiu J, Dai M, Fang Q, Sun X, Gong Y, et al. MicroRNA-351 inhibits denervation-induced muscle atrophy by targeting TRAF6. Exp Ther Med. 2016;12(6):4029–34. https://doi.org/10.3892/etm.2016.3856.CrossRefPubMedPubMedCentral

Title: Exosomal circ-BRWD1 contributes to osteoarthritis development through the modulation of miR-1277/TRAF6 axis
Authors: Zhenye Guo
Huan Wang
Feng Zhao
Min Liu
Feida Wang
Mingming Kang
Weifu He
Zhi Lv
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Osteoarthrosis
Osteoarthrosis
Published in: Arthritis Research & Therapy / Issue 1/2021
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/s13075-021-02541-8

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

Risk of rheumatoid arthritis diagnosis in statin users in a large nationwide US study

Plasma interferon-alpha is associated with double-positivity for autoantibodies but is not a predictor of remission in early rheumatoid arthritis—a spin-off study of the NORD-STAR randomized clinical trial

Change in dietary inflammatory index score is associated with control of long-term rheumatoid arthritis disease activity in a Japanese cohort: the TOMORROW study

bFGF could be a biomarker of malignancy in RS3PE syndrome: an ambispective single-center cohort analysis of 51 patients

The comparative effect of exposure to various risk factors on the risk of hyperuricaemia: diet has a weak causal effect

Lymphatic muscle cells contribute to dysfunction of the synovial lymphatic system in inflammatory arthritis in mice

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials