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PLoS By Category | Recent PLoS Articles
Biochemistry - Rheumatology

Hepatocyte Growth Factor Increases Vascular Endothelial Growth Factor-A Production in Human Synovial Fibroblasts through c-Met Receptor Pathway
Published: Wednesday, November 28, 2012
Author: Yu-Min Lin et al.

by Yu-Min Lin, Yuan-Li Huang, Yi-Chin Fong, Chun-Hao Tsai, Ming-Chih Chou, Chih-Hsin Tang

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.

Methodology/Principal Findings

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-1a activation.

Conclusions/Significance

Taken together, our results provide evidence that HGF enhances VEGF-A expression in OASFs by an HIF-1a-dependent mechanism involving the activation of c-Met/PI3K/Akt and mTORC1 pathways.

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