Ie. James et al., Potent and selective cathepsin L inhibitors do not inhibit human osteoclast resorption in vitro, J BIOL CHEM, 276(15), 2001, pp. 11507-11511
Cathepsins K and L are related cysteine proteases that have been proposed t
o play important roles in osteoclast-mediated bone resorption, To further e
xamine the putative role of cathepsin L in bone resorption, we have evaluat
ed 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 situ cytoch
emical assay (IC50 > 1 muM) and the osteoclast-mediated bone resorption ass
ay (IC50 > 300 nM). Conversely, the cathepsin K selective inhibitor was pot
ently active in both the cytochemical (IC50 = 63 nM) and resorption (IC50 =
71 nM) assays. A recently reported dipeptide aldehyde with activity agains
t cathepsins L (K-i = 0.052 mM) and K (K-i = 1.57 nM) was also active in bo
th assays (IC50 = 110 and 115 nM, respectively) These data confirm that cat
hepsin K and not cathepsin L is the major protease responsible for human os
teoclastic bone resorption.