title: Cartilage oligomeric matrix protein in idiopathic pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive and life threatening disease with median survival of 2.5-3 years. The IPF lung is characterized by abnormal lung remodeling, epithelial cell hyperplasia, myofibroblast foci formation, and extracellular matrix deposition. Analysis of gene expression microarray data revealed that cartilage oligomeric matrix protein (COMP), a non-collagenous extracellular matrix protein is among the most significantly up-regulated genes (Fold change 13, p-value <0.05) in IPF lungs. This finding was confirmed at the mRNA level by nCounter® expression analysis in additional 115 IPF lungs and 154 control lungs as well as at the protein level by western blot analysis. Immunohistochemical analysis revealed that COMP was expressed in dense fibrotic regions of IPF lungs and co-localized with vimentin and around pSMAD3 expressing cells. Stimulation of normal human lung fibroblasts with TGF-β1 induced an increase in COMP mRNA and protein expression. Silencing COMP in normal human lung fibroblasts significantly inhibited cell proliferation and negatively impacted the effects of TGF-β1 on COL1A1 and PAI1. COMP protein concentration measured by ELISA assay was significantly increased in serum of IPF patients compared to controls. Analysis of serum COMP concentrations in 23 patients who had prospective blood draws revealed that COMP levels increased in a time dependent fashion and correlated with declines in force vital capacity (FVC). Taken together, our results should encourage more research into the potential use of COMP as a biomarker for disease activity and TGF-β1 activity in patients with IPF. Hence, studies that explore modalities that affect COMP expression, alleviate extracellular matrix rigidity and lung restriction in IPF and interfere with the amplification of TGF-β1 signaling should be persuaded.
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Vuga
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jadranka
authors.initials: J
authors.lastname: Milosevic
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Kusum
authors.initials: K
authors.lastname: Pandit
authors.affiliation: Pittsburgh Development Center, Magee-Women's Research Institute and Foundation, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Ahmi
authors.initials: A
authors.lastname: Ben-Yehudah
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Richards
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Sciurba
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Myerburg
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Anil V
authors.initials: AV
authors.lastname: Parwani
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gibson
authors.affiliation: Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
mesh_terms: D000368:Aged; D064236:Cartilage Oligomeric Matrix Protein / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D005109:Extracellular Matrix / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D064236:Cartilage Oligomeric Matrix Protein; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D014746:Vimentin; C051321:SERPINE1 protein, human; C497790:SMAD3 protein, human; C577553:TSP5 protein, human