Wilkinson, David J 
ORCID: 0000-0002-6262-3575, Falconer, Adrian MD, Wright, Helen L ORCID: 0000-0003-0442-3134, Lin, Hua, Yamamoto, Kazuhiro ORCID: 0000-0002-8481-775X, Cheung, Kathleen, Charlton, Sarah H, Arques, Maria del Carmen, Janciauskiene, Sabina, Refaie, Ramsay et al (show 3 more authors)
(2022)
Matrix metalloproteinase-13 is fully activated by neutrophil elastase and inactivates its serpin inhibitor, alpha-1 antitrypsin: Implications for osteoarthritis.
FEBS JOURNAL, 289 (1).
pp. 121-139.
ISSN 1742-464X, 1742-4658
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Abstract
Matrix metalloproteinase-13 (MMP-13) is a uniquely important collagenase that promotes the irreversible destruction of cartilage collagen in osteoarthritis (OA). 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-described proteoglycan-degrading 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 ex vivo, in an MMP-dependent manner. In vitro, neutrophil elastase directly and robustly activated pro-MMP-13, and N-terminal sequencing identified cleavage close to the cysteine switch at <sup>72</sup> MKKPR, ultimately resulting in the fully active form with the neo-N terminus of <sup>85</sup> YNVFP. Mole-per-mole, activation was more potent than by MMP-3, 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-1 antitrypsin (gene name SERPINA1), 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-13 specifically inactivated AAT by removal of the serine proteinase cleavage/inhibition site. Taken together, this study identifies elastase as a novel activator of pro-MMP-13 that has relevance for cartilage collagen destruction in OA patients with synovitis.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | alpha-1 antitrypsin, collagen, MMP, neutrophil elastase, osteoarthritis, SERPINA1 |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 22 Jul 2021 07:04 |
| Last Modified: | 06 Dec 2024 19:23 |
| DOI: | 10.1111/febs.16127 |
| Open Access URL: | http://doi.org/10.1111/febs.16127 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3130872 |
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