title: Andrographolide inhibits the migration, invasion and matrix metalloproteinase expression of rheumatoid arthritis fibroblast-like synoviocytes via inhibition of HIF-1α signaling.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacy, Henan Provincial People's Hospital, Zhengzhou 450003, China.
authors.forename: Guo-feng
authors.initials: GF
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Henan Provincial People's Hospital, Zhengzhou 450003, China. Electronic address: YuhuaQin6@163.com.
authors.forename: Yu-hua
authors.initials: YH
authors.lastname: Qin
authors.affiliation: Department of Pharmacy, Henan Provincial People's Hospital, Zhengzhou 450003, China.
authors.forename: Peng-qiang
authors.initials: PQ
authors.lastname: Du
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000473:pathology; D015687:Cell Hypoxia; D002465:Cell Movement; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013583:Synovial Membrane / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004224:Diterpenes; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C030419:andrographolide; D053505:Matrix Metalloproteinases, Secreted
keywords: Hypoxia; Hypoxia-inducible factor-1 alpha (HIF-1α); Invasion; Migration; Rheumatoid arthritis fibroblast synoviocytes (RA-FLSs)