HGF reduces accumulation of collagen I in lung myofibroblasts isolated from Caucasian scleroderma patients via Grb2/Ras/MAPK/MMP‐1‐dependant pathway

• Published in: The FASEB journal 2007, Vol.21 (6), p.A961-A961
• Main Authors: Bogatkevich, Galina S, Ludwicka‐Bradley, Anna, Singleton, C Beth, Silver, Richard M
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.21.6.A961

Hepatocyte growth factor (HGF) is a potent antifibrotic glycoprotein and ligand for c‐Met receptor tyrosine kinase. We found that c‐Met receptor activity is impaired in some lung myofibroblast cell lines particularly in ones isolated from African‐American scleroderma patients, whereas in most Caucasian myofibroblast cell lines HGF demonstrates profound antifibrotic effects. In Caucasian myofibroblasts HGF activates MAPK and PI3K signaling pathways, matrix metalloproteinase (MMP)‐1, and significantly down regulates accumulation of collagen I in time and concentration‐dependent manners. SH3 binding sequence of guanine nucleotide exchange factor hSOS, which blocks SOS/Grb2 interaction and thereby prevents Ras activation via c‐Met receptor, inhibits HGF‐induced Erk1/2 phosphorylation and MMP‐1 activation, and restores HGF‐inhibited collagen accumulation. MAPK inhibitor U0126 prevents HGF’s effects on MMP‐1 and collagen, while PI3K inhibitors do not affect either MMP‐1 or collagen level. We conclude that in lung myofibroblasts HGF down regulates the accumulation of collagen I via c‐Met receptor tyrosine kinase and a Grb2/Ras/MAPK/MMP‐1‐dependant pathway. Support by Scleroderma Foundation, NIH K01 AR051052 and P60 AR049459.