SCIeNtIFIC REPORTS | 7: 16693 | DOI:10.1038/s41598-017-17028-3
The serine proteinase hepsin
is an activator of pro-matrix
mechanisms and implications for
extracellular matrix turnover
David J. Wilkinson
, Antoine Desilets
, Hua Lin
, Sarah Charlton
, Maria del Carmen
, Adrian Falconer
, Craig Bullock
, Yu-Chen Hsu
, Kristian Birchall
, Paul Thompson
, William R. Ferrell
, John Lockhart
, Robin Plevin
, Yadan Zhang
, Shu-Wha Lin
, Richard Leduc
, Jennifer M. Milner
& Andrew D. Rowan
Increasing evidence implicates serine proteinases in the proteolytic cascades leading to the pathological
destruction of extracellular matrices such as cartilage in osteoarthritis (OA). We have previously
demonstrated that the type II transmembrane serine proteinase (TTSP) matriptase acts as a novel
initiator of cartilage destruction via the induction and activation of matrix metalloproteinases (MMPs).
Hepsin is another TTSP expressed in OA cartilage such that we hypothesized this proteinase may
also contribute to matrix turnover. Herein, we demonstrate that addition of hepsin to OA cartilage
in explant culture induced signicant collagen and aggrecan release and activated proMMP-1 and
proMMP-3. Furthermore, hepsin directly cleaved the aggrecan core protein at a novel cleavage site
within the interglobular domain. Hepsin expression correlated with synovitis as well as tumour necrosis
factor α expression, and was induced in cartilage by a pro-inammatory stimulus. However, a major
dierence compared to matriptase was that hepsin demonstrated markedly reduced capacity to
activate proteinase-activated receptor-2. Overall, our data suggest that hepsin, like matriptase, induces
potent destruction of the extracellular matrix whilst displaying distinct eciencies for the cleavage of
Aberrant proteolysis is a characteristic of pathological tissue remodelling events including osteoarthritis (OA),
the most common of arthritic diseases. OA is a progressively degenerative disease causing severe pain, disability
and morbidity. A key characteristic of OA is the breakdown of the cartilage extracellular matrix (ECM), a tissue
that provides smooth surfaces to allow joint articulation. e chondrocyte is the only cell-type responsible for
ECM homeostasis as well as the production of proteinases involved in both health as well as disease. Aggrecan
provides water retention and compressive strength via its hydrophilic properties whilst type II collagen provides
structural integrity. A subset of the matrix metalloproteinases (MMPs), the collagenases (predominantly MMP-1
Skeletal Research Group, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon
Tyne, NE1 3BZ, UK.
Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut
de Pharmacologie, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
Department of Clinical
Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
Bioscience Catalyst, Gunnels Wood Road, Stevenage, SG1 2FX, UK.
Institute for Cell and Molecular Biosciences,
Newcastle University, Newcastle upon Tyne, UK.
Institute of Infection, Immunity and Inammation, University
of Glasgow, Glasgow, UK.
Institute of Biomedical and Environmental Health Research, University of the West of
Scotland, Paisley, UK.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde,
Arthritis Research UK Biomechanics and Bioengineering Centre, Cardiff University, Cardiff, UK.
Arthritis Research UK, Copeman House, St Mary’s Gate, Chestereld, Derbyshire, S41 7TD, UK. Correspondence
and requests for materials should be addressed to A.D.R. (email: email@example.com)
Received: 31 August 2017
Accepted: 21 November 2017
Published: xx xx xxxx