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

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...

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Published in:The Journal of biological chemistry 2001-04, Vol.276 (15), p.11507-11511
Main Authors: James, Ian E., Marquis, Robert W., Blake, Simon M., Hwang, Shing Mei, Gress, Catherine J., Ru, Yu, Zembryki, Denise, Yamashita, Dennis S., McQueney, Michael S., Tomaszek, Thaddeus A., Oh, Hye-Ja, Gowen, Maxine, Veber, Daniel F., Lark, Michael W.
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Language:English
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Summary: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 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 (Ki = 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M010684200