title: Hepatocyte growth factor increases vascular endothelial growth factor-A production in human synovial fibroblasts through c-Met receptor pathway.
abstract: BACKGROUND
  Angiogenesis is essential for the progression of osteoarthritis (OA). Hepatocyte growth factor (HGF) is an angiogenic mediator, and it shows elevated levels in regions of OA. However, the relationship between HGF and vascular endothelial growth factor (VEGF-A) in OA synovial fibroblasts (OASFs) is mostly unknown.
  
  
  RESULTS
  Here we found that stimulation of OASFs with HGF induced concentration- and time-dependent increases in VEGF-A expression. Pretreatment with PI3K inhibitor (Ly294002), Akt inhibitor, or mTORC1 inhibitor (rapamycin) blocked the HGF-induced VEGF-A production. Treatment of cells with HGF also increased PI3K, Akt, and mTORC1 phosphorylation. Furthermore, HGF increased the stability and activity of HIF-1 protein. Moreover, the use of pharmacological inhibitors or genetic inhibition revealed that c-Met, PI3K, Akt, and mTORC1 signaling pathways were potentially required for HGF-induced HIF-1α activation.
  
  
  CONCLUSIONS
  Taken together, our results provide evidence that HGF enhances VEGF-A expression in OASFs by an HIF-1α-dependent mechanism involving the activation of c-Met/PI3K/Akt and mTORC1 pathways.
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Lin
authors.forename: Yuan-Li
authors.initials: YL
authors.lastname: Huang
authors.forename: Yi-Chin
authors.initials: YC
authors.lastname: Fong
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Tsai
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Chou
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction; D013583:Synovial Membrane / Q000166:cytology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met