The methods for this study included immunohistochemical labeling of conventional and novel mammalian collagenase (MMP-1, -2, -8, -13, and -14) of the matrix metalloproteinase (MMP) family and other collagenolytic proteinases of the serine (human trypsin-2) and cysteine (cathepsin K) endoproteinase families in corneal specimens of eyes with and without keratoconus. In epithelium, MMP-1 and MMP-13 expression was more extensive and intense in keratoconus than in controls. In keratoconus, MMP-2 was expressed equally in most cells (epithelium, keratocytes, and endothelium) and all layers (Bowman stroma, Descemet membrane), while it was predominantly expressed in the epithelium of control corneas. Similar profiles were seen in keratoconus and controls with respect to MMP-14, while MMP-8 was more likely to be present in controls. Human trypsin-2 was expressed more strongly in keratoconus than in controls, especially in epithelial cells, in the border between stroma and Descemet membrane, and in Bowman layer and Descemet membrane. Cathepsin K immunoreactivity was similar in keratoconus and controls and present in all cells and layers with the exception of Bowman layer. The authors conclude that the most prominent changes in keratoconus in comparison to controls are in the expression of MMP-13, and cathepsin K and human trypsin-2, suggesting a role for a role for these enzymes in intra- and extracellular pathologic destruction, respectively. With respect to enzymes responsible for normal remodeling, MMP-8 expression is impaired in keratoconus, while MMP-2 and MMP-14 expression is similar in keratoconus and controls.—Michael D. Wagoner