Pivotal Role of Matrix Metalloproteinase 13 in Extracellular Matrix Turnover in Idiopathic Pulmonary Fibrosis

Rationale Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by excessive deposition of extracellular matrix (ECM). Objectives We investigated the regulation of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lung fibrosis. Methods MMP and TIMP expression, collagenolytic activity and collagen content was assessed in IPF (n=16) versus donor (n=6) lung homogenates and accomplished by in-situ-zymography for gelatinolytic and collagenolytic activities, combined with MMP antigen detection. Role of MMP13 was assessed employing the bleomycin model of lung fibrosis in MMP-13-/- versus wild-type mice. Measurements and Main Results In IPF, MMPs-1, 2, 7, 9 and 13, but not MMP-8, were significantly upregulated, whereas none of the TIMPs (1–4) were significantly altered. Collagen content was slightly increased and collagenolytic activity was most prominent in the airways and co-localized with MMP-13. We observed an exaggerated early inflammatory response and an augmented lung fibrosis in bleomycin-challenged MMP-13-/- versus wild-type mice, with elevated lung collagen content 28d after bleomycin challenge in the MMP-13-/- mice. Conclusions Our data suggest that i) collagen deposition in IPF lungs is not primarily due to excessive TIMP production, but rather due to overwhelming ECM production in face of an overall increased, but spatially imbalanced collagenolytic activity, ii) preferential distribution of collagenolytic activity, largely MMP-13, in the airways offers an explanation for the development of honeycomb cysts and iii) despite an overall increase in inflammatory cell content the presence of MMP-13 seems to limit the overall extent of ECM deposition in lung fibrosis.

[1]  B. V. Franko,et al.  Derivatives of 3-pyrrolidinols. III. The chemistry, pharmacology, and toxicology of some N-substituted-3-pyrrolidyl alpha-substituted phenylacetates. , 1960, Journal of medicinal and pharmaceutical chemistry.

[2]  J. F. Woessner,et al.  The determination of hydroxyproline in tissue and protein samples containing small proportions of this imino acid. , 1961, Archives of biochemistry and biophysics.

[3]  E. Campbell,et al.  Pericellular proteolysis by neutrophils in the presence of proteinase inhibitors: effects of substrate opsonization , 1988, The Journal of cell biology.

[4]  Y. Okada,et al.  Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema , 1992, Cell.

[5]  J. Woessner.  Quantification of matrix metalloproteinases in tissue samples. , 1995, Methods in enzymology.

[6]  Woessner Jf.  Quantification of matrix metalloproteinases in tissue samples. , 1995 .

[7]  M. Selman,et al.  TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? , 2000, American journal of physiology. Lung cellular and molecular physiology.

[8]  J. Myers,et al.  Nonspecific interstitial pneumonia and the other idiopathic interstitial pneumonias: classification and diagnostic criteria. , 2000, The American journal of surgical pathology.

[9]  T. Betsuyaku,et al.  Gelatinase B is required for alveolar bronchiolization after intratracheal bleomycin. , 2000, The American journal of pathology.

[10]  T. Sorsa,et al.  Evaluation of collagenase activity, matrix metalloproteinase-8, and matrix metalloproteinase-13 in horses with chronic obstructive pulmonary disease. , 2001, American journal of veterinary research.

[11]  M. Selman,et al.  Tumor necrosis factor receptor deficiency alters matrix metalloproteinase 13/tissue inhibitor of metalloproteinase 1 expression in murine silicosis. , 2001, American journal of respiratory and critical care medicine.

[12]  Naftali Kaminski,et al.  Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[13]  U. Costabel,et al.  ATS/ERS international multidisciplinary consensus classification of the idiopathic interstitial pneumonias , 2002, European Respiratory Journal.

[14]  Paul J. Friedman,et al.  American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors , 2002, American journal of respiratory and critical care medicine.

[15]  C. Brinckerhoff,et al.  Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors , 2001, Arthritis Research & Therapy.

[16]  M. Selman,et al.  Idiopathic pulmonary fibrosis: new insights in its pathogenesis. , 2002, The international journal of biochemistry & cell biology.

[17]  David A Lynch,et al.  Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. , 2003, Chest.

[18]  W. Frederiks,et al.  In Situ Localization of Gelatinolytic Activity in the Extracellular Matrix of Metastases of Colon Cancer in Rat Liver Using Quenched Fluorogenic DQ-gelatin , 2003, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[19]  M. Selman,et al.  Unbalanced collagenases/TIMP-1 expression and epithelial apoptosis in experimental lung fibrosis. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[20]  Y. Okada,et al.  Progressive adult-onset emphysema in transgenic mice expressing human MMP-1 in the lung. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[21]  Mahboob Rahman,et al.  Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[22]  S. Nénan,et al.  Macrophage metalloelastase (MMP-12) deficiency does not alter bleomycin-induced pulmonary fibrosis in mice , 2006, Journal of Inflammation.

[23]  Elena Aikawa,et al.  Matrix Metalloproteinase-13/Collagenase-3 Deletion Promotes Collagen Accumulation and Organization in Mouse Atherosclerotic Plaques , 2005, Circulation.

[24]  J. W. Von den Hoff,et al.  Zymographic techniques for the analysis of matrix metalloproteinases and their inhibitors. , 2005, BioTechniques.

[25]  S. Janssens,et al.  What has been learned about the cardiovascular effects of matrix metalloproteinases from mouse models? , 2006, Cardiovascular research.

[26]  J. D’Armiento,et al.  Matrix metalloproteinases in development and disease. , 2006, Birth defects research. Part C, Embryo today : reviews.

[27]  Remodeling in the kidney , 2006, Nature Medicine.

[28]  M. Selman,et al.  Matrix metalloproteases in aberrant fibrotic tissue remodeling. , 2006, Proceedings of the American Thoracic Society.

[29]  M. Lindsey,et al.  Matrix metalloproteinase (MMP)-7 activates MMP-8 but not MMP-13. , 2006, Medicinal chemistry (Shariqah (United Arab Emirates)).

[30]  D. Brenner,et al.  Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis , 2006, Hepatology.

[31]  N. Karavitaki,et al.  What are the markers of aggressiveness in prolactinomas? Changes in cell biology, extracellular matrix components, angiogenesis and genetics. , 2007, European journal of endocrinology.

[32]  Janet S. Lee,et al.  Essential role of MMP-12 in Fas-induced lung fibrosis. , 2007, American journal of respiratory cell and molecular biology.

[33]  J. Heino,et al.  Collagenase-3 (MMP-13) enhances remodeling of three-dimensional collagen and promotes survival of human skin fibroblasts. , 2007, The Journal of investigative dermatology.

[34]  D. Brenner,et al.  Matrix Metalloproteinase Gene Delivery for Liver Fibrosis , 2007, Pharmaceutical Research.

[35]  J. Fallowfield,et al.  Scar-Associated Macrophages Are a Major Source of Hepatic Matrix Metalloproteinase-13 and Facilitate the Resolution of Murine Hepatic Fibrosis1 , 2007, The Journal of Immunology.

[36]  N. Kaminski,et al.  Approaching the degradome in idiopathic pulmonary fibrosis. , 2008, The international journal of biochemistry & cell biology.

[37]  Y. Okada,et al.  Joint diseases and matrix metalloproteinases: a role for MMP-13. , 2008, Current pharmaceutical biotechnology.