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 journalArticle

4 Citations (Scopus)
15 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
Number of pages13
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017

Fingerprint

Serine Proteases
Matrix Metalloproteinases
Extracellular Matrix
Cartilage
Osteoarthritis
Aggrecans
PAR-2 Receptor
Matrix Metalloproteinase 1
Synovitis
hepsin
Peptide Hydrolases
Collagen
Tumor Necrosis Factor-alpha
matriptase
Proteins

Keywords

  • type II transmembrane serine proteinase
  • TTSP
  • matrix metalloproteinases
  • MMPs
  • hepsin
  • osteoarthritis

Cite this

Wilkinson, David J. ; Desilets, Antoine ; Lin, Hua ; Charlton, Sarah ; Del Carmen Arques, Maria ; Falconer, Adrian ; Bullock, Craig ; Hsu, Yu Chen ; Birchall, Kristian ; Hawkins, Alastair ; Thompson, Paul ; Ferrell, William R. ; Lockhart, John ; Plevin, Robin ; Zhang, Yadan ; Blain, Emma ; Lin, Shu Wha ; Leduc, Richard ; Milner, Jennifer M. ; Rowan, Andrew D. / The serine proteinase hepsin is an activator of pro-matrix metalloproteinases : molecular mechanisms and implications for extracellular matrix turnover. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
@article{27cee494f9e24b1e997b0ec9d4c267c4,
title = "The serine proteinase hepsin is an activator of pro-matrix metalloproteinases: molecular mechanisms and implications for extracellular matrix turnover",
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.",
keywords = "type II transmembrane serine proteinase, TTSP, matrix metalloproteinases , MMPs, hepsin, osteoarthritis",
author = "Wilkinson, {David J.} and Antoine Desilets and Hua Lin and Sarah Charlton and {Del Carmen Arques}, Maria and Adrian Falconer and Craig Bullock and Hsu, {Yu Chen} and Kristian Birchall and Alastair Hawkins and Paul Thompson and Ferrell, {William R.} and John Lockhart and Robin Plevin and Yadan Zhang and Emma Blain and Lin, {Shu Wha} and Richard Leduc and Milner, {Jennifer M.} and Rowan, {Andrew D.}",
year = "2017",
month = "12",
day = "1",
doi = "10.1038/s41598-017-17028-3",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
number = "1",

}

Wilkinson, DJ, Desilets, A, Lin, H, Charlton, S, Del Carmen Arques, M, Falconer, A, Bullock, C, Hsu, YC, Birchall, K, Hawkins, A, Thompson, P, Ferrell, WR, Lockhart, J, Plevin, R, Zhang, Y, Blain, E, Lin, SW, Leduc, R, Milner, JM & Rowan, AD 2017, 'The serine proteinase hepsin is an activator of pro-matrix metalloproteinases: molecular mechanisms and implications for extracellular matrix turnover', Scientific Reports, vol. 7, no. 1, 16693. https://doi.org/10.1038/s41598-017-17028-3

The serine proteinase hepsin is an activator of pro-matrix metalloproteinases : molecular mechanisms and implications for extracellular matrix turnover. / Wilkinson, David J.; Desilets, Antoine; Lin, Hua; Charlton, Sarah; Del Carmen Arques, Maria; Falconer, Adrian; Bullock, Craig; Hsu, Yu Chen; Birchall, Kristian; Hawkins, Alastair; Thompson, Paul; Ferrell, William R.; Lockhart, John; Plevin, Robin; Zhang, Yadan; Blain, Emma; Lin, Shu Wha; Leduc, Richard; Milner, Jennifer M.; Rowan, Andrew D.

In: Scientific Reports, Vol. 7, No. 1, 16693, 01.12.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The serine proteinase hepsin is an activator of pro-matrix metalloproteinases

T2 - molecular mechanisms and implications for extracellular matrix turnover

AU - Wilkinson, David J.

AU - Desilets, Antoine

AU - Lin, Hua

AU - Charlton, Sarah

AU - Del Carmen Arques, Maria

AU - Falconer, Adrian

AU - Bullock, Craig

AU - Hsu, Yu Chen

AU - Birchall, Kristian

AU - Hawkins, Alastair

AU - Thompson, Paul

AU - Ferrell, William R.

AU - Lockhart, John

AU - Plevin, Robin

AU - Zhang, Yadan

AU - Blain, Emma

AU - Lin, Shu Wha

AU - Leduc, Richard

AU - Milner, Jennifer M.

AU - Rowan, Andrew D.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - type II transmembrane serine proteinase

KW - TTSP

KW - matrix metalloproteinases

KW - MMPs

KW - hepsin

KW - osteoarthritis

U2 - 10.1038/s41598-017-17028-3

DO - 10.1038/s41598-017-17028-3

M3 - Article

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 16693

ER -