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Collagenase activation is a key control point for cartilage breakdown to occur, yet our understanding of the proteinases involved in this process is limited. Neutrophil elastase (NE) is a well\u2010described proteoglycan\u2010degrading enzyme which is historically associated with inflammatory arthritis, but more recent evidence suggests a potential role in OA. In this study, we investigated the effect of neutrophil elastase on OA cartilage collagen destruction and collagenase activation. Neutrophil elastase induced significant collagen destruction from human OA cartilage\n                    <jats:italic>ex\u00a0vivo<\/jats:italic>\n                    , in an MMP\u2010dependent manner.\n                    <jats:italic>In\u00a0vitro<\/jats:italic>\n                    , neutrophil elastase directly and robustly activated pro\u2010MMP\u201013, and N\u2010terminal sequencing identified cleavage close to the cysteine switch at\n                    <jats:sup>72<\/jats:sup>\n                    MKKPR, ultimately resulting in the fully active form with the neo\u2010N terminus of\n                    <jats:sup>85<\/jats:sup>\n                    YNVFP. Mole\u2010per\u2010mole, activation was more potent than by MMP\u20103, a classical collagenase activator. Elastase was detectable in human OA synovial fluid and OA synovia which displayed histologically graded evidence of synovitis. Bioinformatic analyses demonstrated that, compared with other tissues, control cartilage exhibited remarkably high transcript levels of the major elastase inhibitor, (AAT) alpha\u20101 antitrypsin (gene name\n                    <jats:italic>SERPINA1<\/jats:italic>\n                    ), but these were reduced in OA. AAT was located predominantly in superficial cartilage zones, and staining enhanced in regions of cartilage damage. Finally, active MMP\u201013 specifically inactivated AAT by removal of the serine proteinase cleavage\/inhibition site. Taken together, this study identifies elastase as a novel activator of pro\u2010MMP\u201013 that has relevance for cartilage collagen destruction in OA patients with synovitis.\n                  <\/jats:p>","DOI":"10.1111\/febs.16127","type":"journal-article","created":{"date-parts":[[2021,7,16]],"date-time":"2021-07-16T12:19:33Z","timestamp":1626437973000},"page":"121-139","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Matrix metalloproteinase\u201013 is fully activated by neutrophil elastase and inactivates its serpin inhibitor, alpha\u20101 antitrypsin: Implications for osteoarthritis"],"prefix":"10.1111","volume":"289","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6262-3575","authenticated-orcid":false,"given":"David J.","family":"Wilkinson","sequence":"first","affiliation":[{"name":"Institute of Life Course and Medical Sciences University of Liverpool UK"},{"name":"Skeletal Research Group Institute of Genetic Medicine Newcastle University UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian M. 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