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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 \u03b1 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.<\/jats:p>","DOI":"10.1038\/s41598-017-17028-3","type":"journal-article","created":{"date-parts":[[2017,11,27]],"date-time":"2017-11-27T09:49:59Z","timestamp":1511776199000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["The serine proteinase hepsin is an activator of pro-matrix metalloproteinases: molecular mechanisms and implications for extracellular matrix turnover"],"prefix":"10.1038","volume":"7","author":[{"given":"David J.","family":"Wilkinson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5081-5564","authenticated-orcid":false,"given":"Antoine","family":"Desilets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Charlton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"del Carmen Arques","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Falconer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Bullock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chen","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Birchall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alastair","family":"Hawkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Ferrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Lockhart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Plevin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yadan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Blain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Wha","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Leduc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M.","family":"Milner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"Rowan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,12,1]]},"reference":[{"key":"17028_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1517\/14728222.12.1.1","volume":"12","author":"AD Rowan","year":"2008","unstructured":"Rowan, A. D., Litherland, G. J., Hui, W. & Milner, J. M. Metalloproteases as potential therapeutic targets in arthritis treatment. Expert Opin Ther Targets \n                           12, 1\u201318, https:\/\/doi.org\/10.1517\/14728222.12.1.1 (2008).","journal-title":"Expert Opin Ther Targets"},{"key":"17028_CR2","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1002\/path.1711300304","volume":"130","author":"RW Jubb","year":"1980","unstructured":"Jubb, R. W. & Fell, H. B. The breakdown of collagen by chondrocytes. J Pathol \n                           130, 159\u2013167, https:\/\/doi.org\/10.1002\/path.1711300304 (1980).","journal-title":"J Pathol"},{"key":"17028_CR3","doi-asserted-by":"publisher","first-page":"2859","DOI":"10.1172\/JCI118357","volume":"96","author":"AP Hollander","year":"1995","unstructured":"Hollander, A. P. et al. 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Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis. Arthritis Rheum \n                           62, 1955\u20131966, https:\/\/doi.org\/10.1002\/art.27476 (2010).","journal-title":"Arthritis Rheum"},{"key":"17028_CR6","doi-asserted-by":"publisher","unstructured":"Wilkinson, D. J. et al. Matriptase induces metalloproteinase-dependent aggrecanolysis in vitro and in vivo: multiple mechanisms promote cartilage damage in osteoarthritis. Arthritis Rheumatol, https:\/\/doi.org\/10.1002\/art.40133 (2017).","DOI":"10.1002\/art.40133"},{"key":"17028_CR7","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1172\/JCI16913","volume":"111","author":"WR Ferrell","year":"2003","unstructured":"Ferrell, W. R. et al. Essential role for proteinase-activated receptor-2 in arthritis. 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