Potent and Selective Cathepsin L Inhibitors Do Not Inhibit Human Osteoclast Resorption in Vitro

Abstract

Cathepsins K and L are related cysteine proteases that have been proposed to play important roles in osteoclast-mediated bone resorption. To further examine the putative role of cathepsin L in bone resorption, we have evaluated selective and potent inhibitors of human cathepsin L and cathepsin K in an in vitro assay of human osteoclastic resorption and an in situ assay of osteoclast cathepsin activity. The potent selective cathepsin L inhibitors (Ki = 0.0099, 0.034, and 0.27 nM) were inactive in both the in situ cytochemical assay (IC50 > 1 μM) and the osteoclast-mediated bone resorption assay (IC50 > 300 nM). Conversely, the cathepsin K selective inhibitor was potently active in both the cytochemical (IC 50 = 63 nM) and resorption (IC50 = 71 nM) assays. A recently reported dipeptide aldehyde with activity against cathepsins L (K i = 0.052 nM) and K (Ki = 1.57 nM) was also active in both assays (IC50 = 110 and 115 nM, respectively) These data confirm that cathepsin K and not cathepsin L is the major protease responsible for human osteoclastic bone resorption.