['Cartilage degradation in osteoarthritis (OA) generates the type II collagen fragments, Helix-II and CTX-II that can be used as clinical biological markers. Helix-II and C-telopeptide of type II collagen (CTX-II) levels are associated independently with progression of OA suggesting that they may be generated through different collagenolytic pathways. In this study we analyzed the release of Helix-II and CTX-II from human cartilage collagen by the proteinases reported to play a role in cartilage degradation.', 'In vitro, human articular cartilage extract was incubated with activated human recombinant cathepsins (Cats) and matrix-metalloproteases (MMPs). Next, we analyzed the spontaneous release of Helix-II and CTX-II from cartilage sections of patients with knee OA who were immediately deep frozen after joint replacement to preserve endogenous enzyme activity until assay. Cartilage sections were then incubated for up to 84 h in the presence or absence of E-64 and GM6001, inhibitors of cysteine proteases and MMPs, respectively.', 'In vitro, Cats K, L and S generated large amount of Helix-II, but not CTX-II. Cat B generated CTX-II fragment, but destroyed Helix-II immunoreactivity. Cat D was unable to digest intact cartilage. MMPs-1, -3, -7, -9, and -13 efficiently released CTX-II, but only small amount of Helix-II. Neither CTX-II nor Helix-II alone was able to reflect accurately the collagenolytic activity of Cats and MMPs as reflected by the release of hydroxyproline. In OA cartilage explants, E-64 blunted the release of Helix-II whereas the release of CTX-II could be completely abrogated by GM6001 and only partly by E-64.'] Do the type II collagen fragments Helix-II and CTX-II reveal different enzymatic pathways of human cartilage collagen degradation?