Levels of circulating MMP-7 degraded elastin are elevated in pulmonary disorders

Elastin is a signature protein of the lungs. Matrix metalloproteinase-7 (MMP-7) is important in lung defence mechanisms and degrades elastin. However, MMP-7 activity in regard to elastin degradation has never been quantified serologically in patients with lung diseases. An assay for the quantificati...

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Veröffentlicht in:	Clinical biochemistry Jg. 48; H. 16-17; S. 1083 - 1088
Hauptverfasser:	Kristensen, J.H., Larsen, L., Dasgupta, B., Brodmerkel, C., Curran, M., Karsdal, M.A., Sand, J.M.B., Willumsen, N., Knox, A.J., Bolton, C.E., Johnson, S.R., Hägglund, P., Svensson, B., Leeming, D.J.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Elsevier Inc 01.11.2015
Schlagworte:	Aged Animals Case-Control Studies Elastin Elastin - metabolism Female Humans Idiopathic pulmonary fibrosis Idiopathic Pulmonary Fibrosis - blood Idiopathic Pulmonary Fibrosis - metabolism Immunology Lung - metabolism Lung carcinoma Lung Diseases - blood Lung Diseases - metabolism Lung Neoplasms - blood Lung Neoplasms - metabolism Male Matrilysin Matrix Metalloproteinase 7 - blood Metalloproteinases Mice Mice, Inbred BALB C Middle Aged Proteolysis Pulmonology Pulmonology Immunology Elastin Idiopathic pulmonary fibrosis Lung carcinoma Metalloproteinases Matrilysin
ISSN:	0009-9120, 1873-2933
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Abstract	Elastin is a signature protein of the lungs. Matrix metalloproteinase-7 (MMP-7) is important in lung defence mechanisms and degrades elastin. However, MMP-7 activity in regard to elastin degradation has never been quantified serologically in patients with lung diseases. An assay for the quantification of MMP-7 generated elastin fragments (ELM7) was therefore developed to investigate MMP-7 derived elastin degradation in pulmonary disorders such as idiopathic pulmonary fibrosis (IPF) and lung cancer. Monoclonal antibodies (mABs) were raised against eight carefully selected MMP-7 cleavage sites on elastin. After characterisation and validation of the mABs, one mAB targeting the ELM7 fragment was chosen. ELM7 fragment levels were assessed in serum samples from patients diagnosed with IPF (n=123, baseline samples, CTgov reg. NCT00786201), and lung cancer (n=40) and compared with age- and sex-matched controls. The ELM7 assay was specific towards in vitro MMP-7 degraded elastin and the ELM7 neoepitope but not towards other MMP-7 derived elastin fragments. Serum ELM7 levels were significantly increased in IPF (113%, p<0.0001) and lung cancer (96%, p<0.0001) compared to matched controls. MMP-7-generated elastin fragments can be quantified in serum and may reflect pathological lung tissue turnover in several important lung diseases. [Display omitted] •A novel competitive ELISA assay quantifies MMP-7 degraded elastin (ELM7).•ELM7 levels increased 15 times in MMP-7 cleaved elastin compared to intact elastin.•hs-ELM7 levels were elevated in lung cancer and IPF compared to matched controls.
AbstractList	Elastin is a signature protein of the lungs. Matrix metalloproteinase-7 (MMP-7) is important in lung defence mechanisms and degrades elastin. However, MMP-7 activity in regard to elastin degradation has never been quantified serologically in patients with lung diseases. An assay for the quantification of MMP-7 generated elastin fragments (ELM7) was therefore developed to investigate MMP-7 derived elastin degradation in pulmonary disorders such as idiopathic pulmonary fibrosis (IPF) and lung cancer. Monoclonal antibodies (mABs) were raised against eight carefully selected MMP-7 cleavage sites on elastin. After characterisation and validation of the mABs, one mAB targeting the ELM7 fragment was chosen. ELM7 fragment levels were assessed in serum samples from patients diagnosed with IPF (n=123, baseline samples, CTgov reg. NCT00786201), and lung cancer (n=40) and compared with age- and sex-matched controls. The ELM7 assay was specific towards in vitro MMP-7 degraded elastin and the ELM7 neoepitope but not towards other MMP-7 derived elastin fragments. Serum ELM7 levels were significantly increased in IPF (113%, p<0.0001) and lung cancer (96%, p<0.0001) compared to matched controls. MMP-7-generated elastin fragments can be quantified in serum and may reflect pathological lung tissue turnover in several important lung diseases. OBJECTIVESElastin is a signature protein of the lungs. Matrix metalloproteinase-7 (MMP-7) is important in lung defence mechanisms and degrades elastin. However, MMP-7 activity in regard to elastin degradation has never been quantified serologically in patients with lung diseases. An assay for the quantification of MMP-7 generated elastin fragments (ELM7) was therefore developed to investigate MMP-7 derived elastin degradation in pulmonary disorders such as idiopathic pulmonary fibrosis (IPF) and lung cancer.DESIGN AND METHODSMonoclonal antibodies (mABs) were raised against eight carefully selected MMP-7 cleavage sites on elastin. After characterisation and validation of the mABs, one mAB targeting the ELM7 fragment was chosen. ELM7 fragment levels were assessed in serum samples from patients diagnosed with IPF (n=123, baseline samples, CTgov reg. NCT00786201), and lung cancer (n=40) and compared with age- and sex-matched controls.RESULTSThe ELM7 assay was specific towards in vitro MMP-7 degraded elastin and the ELM7 neoepitope but not towards other MMP-7 derived elastin fragments. Serum ELM7 levels were significantly increased in IPF (113%, p<0.0001) and lung cancer (96%, p<0.0001) compared to matched controls.CONCLUSIONSMMP-7-generated elastin fragments can be quantified in serum and may reflect pathological lung tissue turnover in several important lung diseases. Elastin is a signature protein of the lungs. Matrix metalloproteinase-7 (MMP-7) is important in lung defence mechanisms and degrades elastin. However, MMP-7 activity in regard to elastin degradation has never been quantified serologically in patients with lung diseases. An assay for the quantification of MMP-7 generated elastin fragments (ELM7) was therefore developed to investigate MMP-7 derived elastin degradation in pulmonary disorders such as idiopathic pulmonary fibrosis (IPF) and lung cancer. Monoclonal antibodies (mABs) were raised against eight carefully selected MMP-7 cleavage sites on elastin. After characterisation and validation of the mABs, one mAB targeting the ELM7 fragment was chosen. ELM7 fragment levels were assessed in serum samples from patients diagnosed with IPF (n=123, baseline samples, CTgov reg. NCT00786201), and lung cancer (n=40) and compared with age- and sex-matched controls. The ELM7 assay was specific towards in vitro MMP-7 degraded elastin and the ELM7 neoepitope but not towards other MMP-7 derived elastin fragments. Serum ELM7 levels were significantly increased in IPF (113%, p<0.0001) and lung cancer (96%, p<0.0001) compared to matched controls. MMP-7-generated elastin fragments can be quantified in serum and may reflect pathological lung tissue turnover in several important lung diseases. [Display omitted] •A novel competitive ELISA assay quantifies MMP-7 degraded elastin (ELM7).•ELM7 levels increased 15 times in MMP-7 cleaved elastin compared to intact elastin.•hs-ELM7 levels were elevated in lung cancer and IPF compared to matched controls.
Author	Curran, M. Knox, A.J. Dasgupta, B. Kristensen, J.H. Bolton, C.E. Karsdal, M.A. Leeming, D.J. Willumsen, N. Svensson, B. Hägglund, P. Brodmerkel, C. Johnson, S.R. Sand, J.M.B. Larsen, L.
Author_xml	– sequence: 1 givenname: J.H. surname: Kristensen fullname: Kristensen, J.H. email: jhk@nordicbioscience.com organization: Nordic Bioscience A/S, Herlev, Denmark – sequence: 2 givenname: L. surname: Larsen fullname: Larsen, L. organization: Nordic Bioscience A/S, Herlev, Denmark – sequence: 3 givenname: B. surname: Dasgupta fullname: Dasgupta, B. organization: Janssen Research and Development, LLC, Spring House, PA, USA – sequence: 4 givenname: C. surname: Brodmerkel fullname: Brodmerkel, C. organization: Janssen Research and Development, LLC, Spring House, PA, USA – sequence: 5 givenname: M. surname: Curran fullname: Curran, M. organization: Janssen Research and Development, LLC, Spring House, PA, USA – sequence: 6 givenname: M.A. surname: Karsdal fullname: Karsdal, M.A. organization: Nordic Bioscience A/S, Herlev, Denmark – sequence: 7 givenname: J.M.B. surname: Sand fullname: Sand, J.M.B. organization: Nordic Bioscience A/S, Herlev, Denmark – sequence: 8 givenname: N. surname: Willumsen fullname: Willumsen, N. organization: Nordic Bioscience A/S, Herlev, Denmark – sequence: 9 givenname: A.J. surname: Knox fullname: Knox, A.J. organization: Division of Respiratory Medicine and Respiratory Research Unit, School of Medicine, University of Nottingham, Nottingham, United Kingdom – sequence: 10 givenname: C.E. surname: Bolton fullname: Bolton, C.E. organization: Division of Respiratory Medicine and Respiratory Research Unit, School of Medicine, University of Nottingham, Nottingham, United Kingdom – sequence: 11 givenname: S.R. surname: Johnson fullname: Johnson, S.R. organization: Division of Respiratory Medicine and Respiratory Research Unit, School of Medicine, University of Nottingham, Nottingham, United Kingdom – sequence: 12 givenname: P. surname: Hägglund fullname: Hägglund, P. organization: The Technical University of Denmark, Department of Systems Biology, Kgs. Lyngby, Denmark – sequence: 13 givenname: B. surname: Svensson fullname: Svensson, B. organization: The Technical University of Denmark, Department of Systems Biology, Kgs. Lyngby, Denmark – sequence: 14 givenname: D.J. surname: Leeming fullname: Leeming, D.J. organization: Nordic Bioscience A/S, Herlev, Denmark
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Keywords	Pulmonology Immunology Elastin Idiopathic pulmonary fibrosis Lung carcinoma Metalloproteinases Matrilysin
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Snippet	Elastin is a signature protein of the lungs. Matrix metalloproteinase-7 (MMP-7) is important in lung defence mechanisms and degrades elastin. However, MMP-7... OBJECTIVESElastin is a signature protein of the lungs. Matrix metalloproteinase-7 (MMP-7) is important in lung defence mechanisms and degrades elastin....
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SubjectTerms	Aged Animals Case-Control Studies Elastin Elastin - metabolism Female Humans Idiopathic pulmonary fibrosis Idiopathic Pulmonary Fibrosis - blood Idiopathic Pulmonary Fibrosis - metabolism Immunology Lung - metabolism Lung carcinoma Lung Diseases - blood Lung Diseases - metabolism Lung Neoplasms - blood Lung Neoplasms - metabolism Male Matrilysin Matrix Metalloproteinase 7 - blood Metalloproteinases Mice Mice, Inbred BALB C Middle Aged Proteolysis Pulmonology
Title	Levels of circulating MMP-7 degraded elastin are elevated in pulmonary disorders
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