Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vitro and in vivo.
We have shown previously that cathepsin K, a recently identified member of the papain superfamily of cysteine proteases, is expressed selectively in osteoclasts and is the predominant cysteine protease in these cells. Based upon its abundant cell type-selective expression, potent endoprotease activity at low pH and cellular localization at the bone interface, cathepsin K has been proposed to play a specialized role in osteoclast-mediated bone resorption. In this study, we evaluated a series of peptide aldehydes and demonstrated that they are potent cathepsin K inhibitors. These compounds inhibited osteoclast-mediated bone resorption in fetal rat long bone (FRLB) organ cultures in vitro in a concentration-dependent manner. Selected compounds were also shown to inhibit bone resorption in a human osteoclast-mediated assay in vitro. Chz-Leu-Leu-Leu-H (in vitro enzyme inhibition Ki,app = 1.4 nM) inhibited parathyroid hormone (PTH)-stimulated resorption in the FRLB assay with an IC-50 of 20 nM and inhibited resorption by isolated human osteoclasts cultured on bovine cortical bone slices with an IC-50 of 100 nM. In the adjuvant-arthritic (AA) rat model, in situ hybridization studies demonstrated high levels of cathepsin K expression in osteoclasts at sites of extensive bone loss in the distal tibia. Cbz-Leu-Leu-Leu-H (30 mg/kg, intraperitoneally) significantly reduced this bone loss, as well as the associated hind paw edema. In the thyroparathyriodectomized rat model, Cbz-Leu-Leu-Leu-H inhibited the increase in blood ionized calcium induced by a 6 h infusion of PTH. These data indicate that inhibitors of cathepsin K are effective at reducing osteoclast-mediated bone resorption and may have therapeutic potential in diseases of excessive bone resorption such as rheumatoid arthritis or osteoporosis.
Votta
B J
BJ
Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Levy
M A
MA
Badger
A
A
Bradbeer
J
J
Dodds
R A
RA
James
I E
IE
Thompson
S
S
Bossard
M J
MJ
Carr
T
T
Connor
J R
JR
Tomaszek
T A
TA
Szewczuk
L
L
Drake
F H
FH
Veber
D F
DF
Gowen
M
M
D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism; D001862:Bone Resorption; D002118:Calcium / Q000097:blood; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002417:Cattle; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology*; D010281:Parathyroid Hormone / Q000494:pharmacology; D016105:Parathyroidectomy; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013965:Thyroidectomy; D014407:Tumor Cells, Cultured
D000447:Aldehydes; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D011994:Recombinant Proteins; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat; D002118:Calcium