Andrographolide inhibits the migration, invasion and matrix metalloproteinase expression of rheumatoid arthritis fibroblast-like synoviocytes via inhibition of HIF-1α signaling

Life Sci. 2015 Sep 1;136:67-72. doi: 10.1016/j.lfs.2015.06.019. Epub 2015 Jul 2.


Aims: Hypoxia is implicated in the pathogenesis of rheumatoid arthritis (RA), contributing to the tumor-like phenotypes of RA fibroblast-like synoviocytes (RA-FLSs). Andrographolide is the main bioactive component of Andrographis paniculata, an herbal medicine that shows therapeutic benefits in RA patients. Here, we explored the effects of andrographolide on hypoxia-induced migration and invasion of RA-FLSs.

Materials and methods: RA-FLSs were exposed to hypoxia in the presence or absence of andrographolide and cell migration and invasion were tested by Transwell assays. The expression of hypoxia-inducible factor-1 alpha (HIF-1α), matrix metalloproteinase (MMP)-1, MMP-3 and MMP-9 was measured by semi-quantitative reverse transcription polymerase chain reaction and Western blot analysis. HIF-1α DNA binding activity was assessed by electrophoretic mobility shift assay. The effects of overexpression of exogenous HIF-1α on the action of andrographolide in RA-FLSs were investigated.

Key findings: Andrographolide inhibited FLS migration and invasion under hypoxic conditions in a dose-dependent manner. The upregulation of MMP-1, MMP-3 and MMP-9 in response to hypoxia was significantly (P<0.05) attenuated by andrographolide. Moreover, the expression and DNA binding activity of HIF-1α were dose-dependently decreased in andrographolide-treated cells under hypoxic conditions. Overexpression of HIF-1α almost completely reversed the suppressive effects of andrographolide on the migration, invasion and MMP expression of hypoxic RA-FLSs.

Significance: These results indicate the ability of andrographolide to attenuate hypoxia-induced invasiveness of RA-FLSs via inhibition of HIF-1α signaling, and warrant further exploration of andrographolide for the treatment of RA.

Keywords: Hypoxia; Hypoxia-inducible factor-1 alpha (HIF-1α); Invasion; Migration; Rheumatoid arthritis fibroblast synoviocytes (RA-FLSs).

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Arthritis, Rheumatoid / pathology
  • Cell Hypoxia
  • Cell Movement
  • Cells, Cultured
  • Diterpenes / pharmacology*
  • Drug Evaluation, Preclinical
  • Enzyme Induction
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Gene Expression / drug effects
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Matrix Metalloproteinases, Secreted / genetics
  • Matrix Metalloproteinases, Secreted / metabolism*
  • Signal Transduction
  • Synovial Membrane / pathology


  • Anti-Inflammatory Agents, Non-Steroidal
  • Diterpenes
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • andrographolide
  • Matrix Metalloproteinases, Secreted