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

Lookup NU author(s): Dr David Wilkinson, Hua LinORCiD, Sarah Charlton, Dr Adrian Falconer, Dr Craig Bullock, Professor Alastair Hawkins, Paul Thompson, Professor Ricahrd Leduc, Dr Jenny Milner, Emeritus Professor Drew Rowan

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Abstract

© 2017 The Author(s).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.

Publication metadata

Author(s): Wilkinson DJ, Desilets A, Lin H, Charlton S, Del Carmen Arques M, Falconer A, Bullock C, Hsu Y-C, Birchall K, Hawkins A, Thompson P, Ferrell WR, Lockhart J, Plevin R, Zhang Y, Blain E, Lin S-W, Leduc R, Milner JM, Rowan AD

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2017

Volume: 7

Issue: 1

Online publication date: 01/12/2017

Acceptance date: 21/11/2017

Date deposited: 18/12/2017

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41598-017-17028-3

DOI: 10.1038/s41598-017-17028-3

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