Growth and rupture of abdominal aortic aneurysms (AAAs) result from increased collagen turnover . Collagen turnover critically depends on specific collagenases that cleave the triple helical region of fibrillar collagen. As yet , the collagenases responsible for collagen degradation in AAAs have not been identified. Increased type I collagen degradation products confirmed collagen turnover in AAAs (median values: <1 , 43 , and 108 ng/mg protein in control , growing , and ruptured AAAs , respectively). mRNA and protein analysis identified neutrophil collagenase [matrix metalloproteinase (MMP)-8] and cysteine collagenases cathepsin K , L , and S as the principle collagenases in growing and ruptured AAAs. Except for modestly increased MMP-14 mRNA levels , collagenase expression was similar in growing and ruptured AAAs (anteriorlateral wall). Evaluation of posttranslational regulation of protease activity showed a threefold increase in MMP-8 , a fivefold increase in cathepsins K and L , and a 30-fold increase in cathepsin S activation in growing and ruptured AAAs. The presence of the osteoclastic proton pump indicated optimal conditions for extracellular cysteine protease activity. Protease inhibitor mRNA expression was similar in AAAs and controls, but AAA protein levels of cystatin C, the principle cysteine protease inhibitor, were profoundly reduced (>80%). We found indications that this secondary deficiency relates to cystatin C degradation by (neutrophil-derived) proteases. Abdominal aortic aneurysm (AAA) is a common pathology and a major cause of death because of rupture. 1,2 The hallmark pathology of AAA is a persistent proteolytic imbalance that results in excess matrix destruction and progressive weakening of the arterial wall. A number of matrix metalloproteinases (MMPs) (in particular the gelatinases MMP-2 and -9) 1,3 have been implicated as primary proteolytic culprits in the disease, but it is dubious whether these proteases are directly responsible for the weakening and ultimate failure of the aortic wall. Biomechanical studies invariably show that the mechanical stability of the arterial wall essentially relies on fibrillar collagens in media and adventitia. 4 -6 These structural collagens are highly resistant toward proteolytic degradation, and the only mammalian proteases that have been shown to cleave the native triple helical region of fibrillar collagen are the classic collagenases of the MMP family 7 [ie, MMP-1, -8, and -13 and the membrane type-1 MMP (MT-1 MMP or MMP-14 8 )], as well as selected members of the cysteine protease family (ie, cathepsin K, 9,10 L, 11 and possibly S 12 ).Several reports indicate expression of these collagenases in AAA on an individual basis, but comparative data regarding expression of the collagenases, and their possible relationship to rupture of the aneurysm, 13,14 are not available. Moreover, available studies 15 do not address the critical and complex posttranslational regulation of protease activity that involves controlled secretion of an inactive proenzyme,...