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 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.
James
I E
IE
Departments of Bone and Cartilage Biology, Medicinal Chemistry, Protein Biochemistry, and Mechanistic Enzymology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. ian_e_james@sbphrd.com
Marquis
R W
RW
Blake
S M
SM
Hwang
S M
SM
Gress
C J
CJ
Ru
Y
Y
Zembryki
D
D
Yamashita
D S
DS
McQueney
M S
MS
Tomaszek
T A
TA
Oh
H J
HJ
Gowen
M
M
Veber
D F
DF
Lark
M W
MW
D001862:Bone Resorption; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D010450:Endopeptidases; D006801:Humans; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L