The serine proteinase hepsin is an activator of pro-matrix metalloproteinases: molecular mechanisms and implications for extracellular matrix turnover

David J. Wilkinson, Antoine Desilets, Hua Lin, Sarah Charlton, Maria del Carmen Arques, Adrian Falconer, Craig Bullock, Yu-Chen Hsu, Kristian Birchall, Alastair Hawkins, Paul Thompson, William R. Ferrell, John Lockhart, Robin Plevin, Yadan Zhang, Emma Blain, Shu-Wha Lin, Richard Leduc, Jennifer M. Milner, Andrew D. Rowan

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)
108 Downloads (Pure)

Abstract

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 significant 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-inflammatory stimulus. However, a major difference 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
efficiencies for the cleavage of specific substrates.
Original languageEnglish
Article number16693
Pages (from-to)1-38
Number of pages38
JournalScientific Reports
Volume7
Early online date1 Dec 2017
DOIs
Publication statusE-pub ahead of print - 1 Dec 2017

Keywords

  • Hepsin
  • PAR2
  • matrix

Fingerprint

Dive into the research topics of 'The serine proteinase hepsin is an activator of pro-matrix metalloproteinases: molecular mechanisms and implications for extracellular matrix turnover'. Together they form a unique fingerprint.

Cite this