Molecular mechanisms of MMP9 overexpression and its role in emphysema pathogenesis of Smad3-deficient mice

Xu B, Chen H, Xu W, Zhang W, Buckley S, Zheng SG, Warburton D, Kolb M, Gauldie J, Shi W. Molecular mechanisms of MMP9 overexpression and its role in emphysema pathogenesis of Smad3-deficient mice. Am J Physiol Lung Cell Mol Physiol 303: L89-L96, 2012. First published May 18, 2012; doi:10.1152/ajplung.00060.2012.-Previous studies have found that inappropriate elevation of matrix metalloproteinase-9 (MMP9) expression and activity is coincident with early onset of emphysema in Smad3-null mice. Herein, we further investigated the role of increased MMP9 in emphysema pathogenesis and the related molecular regulatory mechanisms of elevated MMP9 in Smad3-null lung. Genetic blockade of MMP9 in Smad3-null mice significantly attenuated emphysema pathology but not hypoalveolarization during early postnatal lung development. Furthermore, Smad3 was found to be a transcription factor to positively regulate a protein deacetylase sirtuin 1 (SIRT1) by binding to an AP-1 site of SIRT1 promoter. A synergistic regulatory effect on SIRT1 expression was also detected between Smad3 and c-Jun. Consistently, Smad3 knockout lung at P28 had reduced SIRT1 expression, which in turn resulted in increased acetylation of histone H3 at the transcription factor activator protein 1 (AP-1), NF-kappa B, and Pea3 binding sites of MMP9 promoter and increased acetylation of NF-kappa B. In addition, increased Pea3 expression and nuclear accumulation was also detected in Smad3-null lungs at P28. Consistently, bindings of acetylated NF-kappa B and Pea3 to the MMP9 promoter were elevated in Smad3-null lung. We thus propose that deficiency of Smad3 causes downregulation of SIRT1 and increased Pea3 expression/nuclear accumulation, respectively. Decreased SIRT1 activity resulted in increased acetylation of histone H3 and NF-kappa B. Subsequently, increased bindings of transcription factors including NF-kappa B and Pea3 to MMP9 promoter significantly upregulate MMP9 transcription, contributing to emphysema pathogenesis.