title: Peroxidase enzymes regulate collagen extracellular matrix biosynthesis.
abstract: Myeloperoxidase and eosinophil peroxidase are heme-containing enzymes often physically associated with fibrotic tissue and cancer in various organs, without any direct involvement in promoting fibroblast recruitment and extracellular matrix (ECM) biosynthesis at these sites. We report herein novel findings that show peroxidase enzymes possess a well-conserved profibrogenic capacity to stimulate the migration of fibroblastic cells and promote their ability to secrete collagenous proteins to generate a functional ECM both in vitro and in vivo. Mechanistic studies conducted using cultured fibroblasts show that these cells are capable of rapidly binding and internalizing both myeloperoxidase and eosinophil peroxidase. Peroxidase enzymes stimulate collagen biosynthesis at a post-translational level in a prolyl 4-hydroxylase-dependent manner that does not require ascorbic acid. This response was blocked by the irreversible myeloperoxidase inhibitor 4-amino-benzoic acid hydrazide, indicating peroxidase catalytic activity is essential for collagen biosynthesis. These results suggest that peroxidase enzymes, such as myeloperoxidase and eosinophil peroxidase, may play a fundamental role in regulating the recruitment of fibroblast and the biosynthesis of collagen ECM at sites of normal tissue repair and fibrosis, with enormous implications for many disease states where infiltrating inflammatory cells deposit peroxidases.
authors.affiliation: Breast Cancer Research Unit, Discipline of Surgery, The University of Adelaide, Adelaide, South Australia, Australia. Electronic address: mark.denichilo@adelaide.edu.au.
authors.forename: Mark O
authors.initials: MO
authors.lastname: DeNichilo
authors.affiliation: Breast Cancer Research Unit, Discipline of Surgery, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Panagopoulos
authors.affiliation: Paramedic Unit, Flinders Clinical Effectiveness, School of Medicine, Flinders University, Bedford Park, South Australia, Australia.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Rayner
authors.affiliation: Mesenchymal Stem Cell Laboratory, School of Medical Sciences, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Romana A
authors.initials: RA
authors.lastname: Borowicz
authors.affiliation: Adult Burn Centre, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: John E
authors.initials: JE
authors.lastname: Greenwood
authors.affiliation: Breast Cancer Research Unit, Discipline of Surgery, The University of Adelaide, Adelaide, South Australia, Australia; Center for Personalized Cancer Medicine, The University of Adelaide, Adelaide, South Australia, Australia. Electronic address: andreas.evdokiou@adelaide.edu.au.
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D047209:Eosinophil Peroxidase / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D009195:Peroxidase / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D034421:Sus scrofa
chemical_list: D003094:Collagen; D047209:Eosinophil Peroxidase; D009195:Peroxidase