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

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-FLSswere 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-1 alpha), matrix metalloproteinase (MMP)-1, MMP-3 and MMP-9 was measured by semi-quantitative reverse transcription polymerase chain reaction and Western blot analysis. HIF-1 alpha DNA binding activity was assessed by electrophoretic mobility shift assay. The effects of overexpression of exogenous HIF-1 alpha 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-1 alpha were dose-dependently decreased in andrographolide-treated cells under hypoxic conditions. Overexpression of HIF-1 alpha 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-1 alpha signaling, and warrant further exploration of andrographolide for the treatment of RA. (C) 2015 Elsevier Inc. All rights reserved.