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 (K i = 0.0099, 0.034, and 0.27 nm) were inactive in both the in situcytochemical 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 (IC50 = 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 (K i = 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.