4.5 Article

Elevated microRNA-145-5p increases matrix metalloproteinase-9 by activating the nuclear factor-κB pathway in rheumatoid arthritis

Journal

MOLECULAR MEDICINE REPORTS
Volume 20, Issue 3, Pages 2703-2711

Publisher

SPANDIDOS PUBL LTD
DOI: 10.3892/mmr.2019.10499

Keywords

rheumatoid arthritis; MMP-9; microRNA; FLS; NF-kappa B

Funding

  1. National Natural Science Foundation of China [81330029]
  2. Tianjin Medical University General Hospital (Tianjin, China)

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The present study explored whether miR-145-5p can aggravate the development and progression of rheumatoid arthritis (RA) by regulating the expression of matrix metalloproteinases (MMPs). ELISAs, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blotting were used to examine the expression levels of MMP-1, MMP-3, MMP-9, and MMP-13 in fibroblast-like synoviocytes (FLS) from patients with RA. Levels of MMP-1, MMP-3, MMP-9, and MMP-13 were assessed in the right hind ankles of a murine collagen-induced arthritis (CIA) model by RT-qPCR and immunohistochemical (IHC) analysis. The effects of activation or inhibition of the nuclear factor-kappa B (NF-kappa B) pathway on MMPs were evaluated by RT-qPCR and western blotting. Subcellular localization of NF-kappa B p65 was visualized by confocal microscopy. Overexpression of miR-145-5p increased the expression of MMP-3, MMP-9, and MMP-13 in RA-FLS. Moreover, injection of a miR-145-5p agomir into mice increased MMP-3, MMP-9, and MMP-13, as demonstrated by RT-qPCR and IHC analysis. A chemical inhibitor that selectively targets NF-kappa B (BAY11-7082) significantly attenuated MMP-9 expression, while it did not influence the levels of MMP-3 and MMP-13. Immunofluorescence analysis revealed that nuclear localization of p65 was significantly enhanced, indicating that miR-145-5p enhances activation of the NF-kappa B pathway by promoting p65 nuclear translocation. miR-145-5p overexpression also significantly increased phosphorylated p65 levels; however, the levels of IkB-a were reduced in response to this miRNA. Moreover, our results indicated that miR-145-5p aggravated RA progression by activating the NF-kappa B pathway, which enhanced secretion of MMP-9. In conclusion, modulation of miR-145-5p expression is potentially useful for the treatment of RA inflammation, by regulating the expression of MMPs, and MMP-9 in particular, through inhibition of the NF-kappa B pathway.

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