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J Biol Chem. 2001 Apr 13;276(15):11507-11. Epub 2001 Jan 8.

Potent and selective cathepsin L inhibitors do not inhibit human osteoclast resorption in vitro.

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  • 1Departments of Bone and Cartilage Biology, Medicinal Chemistry, Protein Biochemistry, and Mechanistic Enzymology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.

Erratum in

  • J Biol Chem. 2003 Aug 22;278(34):32484.


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 situ cytochemical assay (IC(50) > 1 micrometer) and the osteoclast-mediated bone resorption assay (IC(50) > 300 nm). Conversely, the cathepsin K selective inhibitor was potently active in both the cytochemical (IC(50) = 63 nm) and resorption (IC(50) = 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 (IC(50) = 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.

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