Increased type II collagen cleavage by cathepsin K and collagenase activities with aging and osteoarthritis in human articular cartilage

Fixed frozen cartilage sections were examined immunohistochemically, using antibodies that react with the collagenase-generated cleavage neoepitopes, C2C and C1,2C, and the primary cleavage neoepitope (C2K) generated in type II collagen by the action of cathepsin K and possibly by other proteases, but not by any collagenases studied to date.In most cases, the staining patterns for collagen cleavage were similar for all three epitopes: weak to moderate mainly pericellular staining in non-OA cartilage from younger individuals and stronger, more widespread staining in aging and OA cartilages that often extended from the superficial to the mid/deep zone of the tissue. In very degenerate OA specimens, with significant disruption of the articular surface, staining was distributed throughout most of the cartilage matrix.Cleavage of collagen by proteases usually arises pericellularly around chondrocytes at and near the articular surface, subsequently becoming more intense and extending progressively deeper into the cartilage with aging and OA. The close correspondence between the distributions of these products suggests that both collagenases and cathepsin K, and other proteases that may generate this distinct cathepsin K cleavage site, are usually active in the same sites in the degradation of type II collagen.Type II collagen (Col II), the major structural component of the articular cartilage, is composed of three identical α chains that form collagen fibrils. The mechanical properties and tensile strength of cartilage depend to a large degree on the integrity of the mesh-like endoskeleton formed by bundles of collagen fibrils with different orientations and diameters in each of the four zones of articular cartilage [1]. Under non-inflammatory conditions, collagen turnover is mediated by the only cell type found in articular cartilage, the chondrocyte. Increased catabolic responses in osteoarthritis (OA) mediated by chondrocytes involve enhanced cleavage of type II collag