MicroRNA-146a reduces IL-1 dependent inflammatory responses in the intervertebral disc

Su Xi Gu, Xin Li, John L. Hamilton, Ana Chee, Ranjan Kc, Di Chen, Howard S. An, Jae Sung Kim, Chun do Oh, Yuan Zheng Ma, Andre J. van Wijnen, Hee Jeong Im

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Because miR-146a expression in articular chondrocytes is associated with osteoarthritis (OA), we assessed whether miR-146a is linked to cartilage degeneration in the spine. Monolayer cultures of nucleus pulposus (NP) cells from the intervertebral discs (IVD) of bovine tails were transfected with a miR-146a mimic. To provoke inflammatory responses and catabolic extracellular matrix (ECM) degradation, cells were co-treated with interleukin-1 (IL-1). Transfection of miR-146a decreases IL-1 induced mRNA levels of inflammatory genes and catabolic proteases in NP cells based on quantitative real-time reverse transcriptase PCR (qRT-PCR) analysis. Similarly, miR146a suppresses IL-1 induced protein levels of matrix metalloproteinases and aggrecanases as revealed by immunoblotting. Disc segments from wild type (WT) and miR-146a knockout (KO) mice were cultured ex vivo in the presence or absence of IL-1 for 3. days. Histological and immuno-histochemical (IHC) analyses of disc organ cultures revealed that IL-1 mediates changes in proteoglycan (PG) content and in-situ levels of catabolic proteins (MMP-13 and ADAMTS-5) in the nucleus pulposus of the disc. However, these IL-1 effects are more pronounced in miR-146a KO discs compared to WT discs. For example, absence of miR-146a increases the percentage of MMP-13 and ADAMTS-5 positive cells after treatment with IL-1. Thus, miR-146a appears to protect against IL-1 induced IVD degeneration and inflammation. Stimulation of endogenous miR-146a expression or exogenous delivery of miRNA-146a are viable therapeutic strategies that may decelerate disc degeneration and regain a normal homeostatic balance in extracellular matrix production and turn-over.

Original languageEnglish (US)
Pages (from-to)80-87
Number of pages8
JournalGene
Volume555
Issue number2
DOIs
StatePublished - Jan 25 2015

Keywords

  • ADAMTS-5
  • IL-1
  • Intervertebral disc degeneration
  • MMP-13
  • MiR-146a
  • Nucleus pulposus

ASJC Scopus subject areas

  • Genetics

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