title: Molecular mechanisms of MMP9 overexpression and its role in emphysema pathogenesis of Smad3-deficient mice.
abstract: 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-κB, and Pea3 binding sites of MMP9 promoter and increased acetylation of NF-κB. In addition, increased Pea3 expression and nuclear accumulation was also detected in Smad3-null lungs at P28. Consistently, bindings of acetylated NF-κB 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-κB. Subsequently, increased bindings of transcription factors including NF-κB and Pea3 to MMP9 promoter significantly upregulate MMP9 transcription, contributing to emphysema pathogenesis.
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Children's Hospital Los Angeles, CA 90027, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Wenming
authors.initials: W
authors.lastname: Zhang
authors.forename: Sue
authors.initials: S
authors.lastname: Buckley
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.forename: Martin
authors.initials: M
authors.lastname: Kolb
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
mesh_terms: D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D006657:Histones / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011656:Pulmonary Emphysema / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000172:deficiency* / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D015854:Up-Regulation
chemical_list: D006657:Histones; D016328:NF-kappa B; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C065788:transcription factor PEA3; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1