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Matrix metalloproteinase‐13 is fully activated by neutrophil elastase and inactivates its serpin inhibitor, alpha‐1 antitrypsin: Implications for osteoarthritis
- Source :
- FEBS JOURNAL
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
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 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.
- Subjects :
- Neutrophils
Matrix metalloproteinase
Serpin
Osteochondrodysplasias
Biochemistry
alpha 1-Antitrypsin Deficiency
Matrix Metalloproteinase 13
Osteoarthritis
medicine
Humans
Synovial fluid
Cysteine
Molecular Biology
Inflammation
Synovitis
biology
Chemistry
Cartilage
Elastase
Cell Biology
Molecular biology
Elastase inhibitor
medicine.anatomical_structure
alpha 1-Antitrypsin
Neutrophil elastase
biology.protein
Collagenase
Matrix Metalloproteinase 3
Leukocyte Elastase
medicine.drug
Subjects
Details
- ISSN :
- 17424658 and 1742464X
- Volume :
- 289
- Database :
- OpenAIRE
- Journal :
- The FEBS Journal
- Accession number :
- edsair.doi.dedup.....e4785ea187f1d88a73eb0881ed0702de