microRNA-665 promotes the proliferation and matrix degradation of nucleus pulposus through targeting GDF5 in intervertebral disc degeneration

J Cell Biochem. 2018 Sep;119(9):7218-7225. doi: 10.1002/jcb.26888. Epub 2018 May 15.

Abstract

Growing evidences suggested that microRNAs (miRNAs) played important roles in the development of intervertebral disc degeneration (IDD). However, the expression level and function of miR-665 in IDD remain unknown. In this study, we showed that the expression level of miR-665 was upregulated in degenerative human NP samples. In addition, miR-665 expression level gradually increased with the exacerbation of disc degeneration grade. Moreover, miR-665 expression level was positively associated with the Pfirrmann grade. Ectopic expression of miR-665 promoted NP cell growth. Furthermore, miR-665 overexpression decreased aggrecan and Col II expression and ectopic expression of miR-665 increased MMP-3 and MMP-13 expression in NP cell. We identified growth differentiation factor 5 (GDF5) was a direct target gene of miR-665 in NP cell and enforced expression of miR-665 decreased GDF5 expression. Elevated expression of miR-665 enhanced NP cell proliferation and decreased aggrecan and Col II expression. In addition, ectopic expression of miR-665 increased MMP-3 and MMP-13 expression through inhibiting GDF5 expression in NP cells. These results suggested that dysregulated miR-665 expression might act an important role in the development of IDD.

Keywords: GDF5; intervertebral disc degeneration; miR-665; microRNAs.

MeSH terms

  • Aggrecans / antagonists & inhibitors
  • Aggrecans / metabolism
  • Analysis of Variance
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Ectopic Gene Expression
  • Extracellular Matrix / metabolism*
  • Growth Differentiation Factor 5 / antagonists & inhibitors
  • Growth Differentiation Factor 5 / metabolism*
  • Humans
  • Intervertebral Disc / metabolism
  • Intervertebral Disc Degeneration / metabolism*
  • Matrix Metalloproteinase 13 / metabolism
  • Matrix Metalloproteinase 3 / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism*
  • Molecular Mimicry
  • Nucleus Pulposus / metabolism*
  • Transfection
  • Up-Regulation

Substances

  • ACAN protein, human
  • Aggrecans
  • GDF5 protein, human
  • Growth Differentiation Factor 5
  • MIRN665 microRNA, human
  • MicroRNAs
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • MMP3 protein, human
  • Matrix Metalloproteinase 3