The Effects of Matrix Metalloproteinases on Fetuin's Role as an Inhibitor of Transforming Growth Factor-beta1

Periodontitis may increase the risk of developing cardiovascular diseases, yet mechanisms of this association are undefined. Transforming growth factor beta-1 (TGF-β1) has both atheroprotective and atherogenic roles. Fetuin, a serum glycoprotein, binds and inhibits TGF-β1, which may affect atheroma formation. Some matrix metalloproteinases (MMP) elevated in periodontitis are known to cleave fetuin. We hypothesized that fetuin cleavage by MMPs may reduce fetuin’s ability to inhibit TGF-β1. SDS-PAGE, densitometry and mass spectrometry confirmed bovine fetuin was degraded by MMP-2, 3, 7, and 9 (MMP:fetuin=1:60), identifying unique cleavages. TGF-β1 activity at 2ng/mL was assessed with intact or MMP-cleaved fetuin utilizing a cell growth assay. TGF-β1 inhibited cell growth by 28.6%. Intact fetuin, at 1mg/mL and higher, reduced TGF-β1 inhibition of cell growth to 19.8%. MMP-7-cleaved fetuin, at 0.2mg/mL, significantly reduced the TGF-β1 inhibition to 8.6%. Thus, MMP-7 cleavage of fetuin enhances fetuin’s ability to inhibit TGF-β1.M.Sc