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Lookup NU author(s): Dr David Wilkinson, Dr Adrian Falconer, Hua LinORCiD, Kat Cheung, Sarah Charlton, Dr Maria Arques Mengual, Dr Ramsay Refaie, Dr Kenneth RankinORCiD, Professor David YoungORCiD, Emeritus Professor Drew Rowan
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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 72 MKKPR, ultimately resulting in the fully active form with the neo-N terminus of 85 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.
Author(s): Wilkinson DJ, Falconer AMD, Wright HL, Lin H, Yamamoto K, Cheung K, Charlton SH, Arques MDC, Janciauskiene S, Refaie R, Rankin KS, Young DA, Rowan AD
Publication type: Article
Publication status: Published
Journal: The FEBS Journal
Year: 2021
Volume: 289
Issue: 1
Pages: 121-139
Print publication date: 04/01/2022
Online publication date: 16/07/2021
Acceptance date: 15/07/2021
Date deposited: 15/02/2022
ISSN (print): 1742-464X
ISSN (electronic): 1742-4658
Publisher: Wiley
URL: https://doi.org/10.1111/febs.16127
DOI: 10.1111/febs.16127
Data Access Statement: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE111358
PubMed id: 34270864
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