Neutrophil elastase and its inhibitors-overlooked players in osteoarthritis.

Cartilage homeostasis is maintained by a delicate balance between anabolism and catabolism. In osteoarthritis, pathological biomechanics or injury triggers cartilage breakdown, nonresolving synovial inflammation, and bone changes, causing reduced joint mobility and incapacitating pain. Undoubtedly, the most important cartilage degrading collagenase during osteoarthritis, matrix metalloproteinase (MMP)-13, is activated by an unlikely player: neutrophil elastase. Although primarily associated with inflammatory arthritis, neutrophil elastase is present in the osteoarthritic joint, and through activating MMP-13, spurs a cascade of events leading not just to the aberrant destruction of the cartilage itself, but to the proteolysis of its own inhibitor, alpha-1-antitrypsin, as described in the new study by Wilkinson et al. Endowed with potent chondrogenic and cartilage-protective properties, the loss of alpha-1-antitrypsin from cartilage will have major consequences for osteoarthritis progression, and strategies to prevent its loss, or replace it, might provide an innovative treatment opportunity that should not be ignored. Comment on: https://doi.org/10.1111/febs.16127.