Matrix metalloproteinase‐13 is fully activated by neutrophil elastase and inactivates its serpin inhibitor, alpha‐1 antitrypsin: Implications for osteoarthritis

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 72MKKPR, ultimately resulting in the fully active form with the neo‐N terminus of 85YNVFP. 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.

Instructive cartilage regeneration modalities with advanced therapeutic implantations under abnormal conditions

“…MMP-14 can activate gelatinase, which leads to a chain reaction in cartilage destruction. Therefore, another therapeutic strategy for OA focuses on reducing the secretion of MMPs [ 161 , 162 ]. Targeting MMP inhibitors were thus proposed, aiming to restrain the redundant expression of MMPs in cartilage.…”

Osteoarthritis year in review: genetics, genomics, epigenetics

“…Since heterozygosity for the Z allele reduces AAT levels, this could possibly explain both the lower BMD and associated OA risk. Recently, neutrophil elastase, for which AAT is an inhibitor, has been shown to fully activate MMP13, the major collagenase that promotes the irreversible destruction of cartilage collagen in OA 9 . Active MMP13 can proceed to inactivate AAT, thus AAT may play a complex role in multiple musculoskeletal tissues in OA.…”

Neutrophil elastase and its inhibitors—overlooked players in osteoarthritis

“…The interesting new study by Wilkinson et al . highlights just how damaging neutrophils can be in the inflamed joint: The group reports the presence of large amounts of NE in OA synovial tissues and fluids [6]. Well supported by recent publications [2,3,7,8], NE is now in the limelight as a functional biomarker for osteoarthritis progression.…”

“…Upon reaching the site of inflammation, these immune cells become activated with macrophages secreting inflammatory cytokines and matrix metalloproteinases, while neutrophils release degradative proteases into the joint space, mainly serine proteases, including neutrophil elastase (NE), cathepsin G, and proteinase 3. The interesting new study by Wilkinson et al highlights just how damaging neutrophils can be in the inflamed joint: The group reports the presence of large amounts of NE in OA synovial tissues and fluids [6]. Well supported by recent publications [2,3,7,8], NE is now in the limelight as a functional biomarker for osteoarthritis progression.…”

“…It degrades connective tissue components such as elastin fibers, type IV collagen, proteoglycan, and fibronectin, which could be an attempt to repair acute injury to the joint. However, if left unchecked, NE can cause irreversible damage to cartilage [6,8,9] and subchondral bone, and crucially, can contribute to the development of pain and peripheral neuropathy [8,10].…”