Elastase secreted by activated polymorphonuclear leucocytes causes chondrocyte damage and matrix degradation in intact articular cartilage: escape from inactivation by alpha-1-proteinase inhibitor.
Anatomically intact, murine patellar cartilage was exposed to human polymorphonuclear leucocytes (PMN) stimulated with formyl-methionyl-leucyl-phenylalanine or Ca-ionophore A-23187. This resulted in an inhibition of chondrocyte proteoglycan synthesis and breakdown of cartilage matrix proteoglycans as shown with 35S-incorporation and autoradiography. These effects could not be inhibited by catalase or superoxide dismutase. A serine protease inhibitor and a specific elastase inhibitor prevented both proteoglycan degradation and chondrocyte damage, indicating that PMN-elastase is the causative agent. It was shown that elastase shed by PMN in close contact with the articular cartilage, can escape from complexing with alpha-1 proteinase inhibitor. We would hypothesize that the elastase owing to its dual action (matrix breakdown and inhibition of chondrocyte metabolism) is a major contributor to enzymatic cartilage destruction in inflammatory disorders.
D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000201:enzymology*; D009924:Organ Culture Techniques; D010196:Pancreatic Elastase / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D000515:alpha 1-Antitrypsin
D001798:Blood Proteins; D011480:Protease Inhibitors; D011509:Proteoglycans; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase