A cysteine protease inhibitor prevents suspension-induced declines in bone weight and strength in rats.
In this study, we examined the effects of a potent cysteine protease inhibitor, N-(L-3-trans-carboxyoxirane-2-cabonyl)-L-leucine-4-aminobutylamide (E-64a), on bone weight and strength in tail-suspended rats. We first administered a vehicle or 4 or 8 mg/rat of E-64a to rats fed with a low calcium diet for 7 wks to determine effective doses of E-64a on bone resorption in vivo. Femoral cathepsin K-like activity and serum hydroxyproline level in rats fed with a low calcium diet were significantly higher than those in rats fed with a standard diet. The intraperitoneal injection of 8 mg/rat of E-64a to rats decreased their serum calcium and hydroxyproline concentrations after 3 to 6 hrs in parallel with changes in femoral cathepsin K-like activity, while 4 mg/rat of E-64a had weaker effects on these parameters. Based on these results, we injected 8 mg/rat of E-64a to tail-suspended rats twice a day for 2 wks and compared the results with those of treatment with 1 mg/rat of etidronate, a bisphosphonate, twice a week. In tail-suspended rats, femoral weight and strength, assessed by three-point bending test, significantly decreased from Day 5 to 21, while femoral cathepsin K-like activity and serum calcium and hydroxyproline concentrations did not change. E-64a inhibited femoral cathepsin K-like activity in tail-suspended rats, but etidronate did not. E-64a as well as etidronate significantly prevented the suspension-induced declines in bone weight and strength. However, more frequent injection and higher doses were required for E-64a to exhibit significant efficacy of antiresorption, compared with those of etidronate. Our results suggest that a cysteine protease inhibitor could improve suspension-induced osteopenia by inhibiting cathepsin K-like activity in bone; however, it needs several improvements in the effect as a clinical drug.
Nikawa
Takeshi
T
Department of Nutrition, School of Medicine, University of Tokushima. nikawa@nutr.med.tokushima-u.ac.jp
Ikemoto
Madoka
M
Watanabe
Chiho
C
Kitano
Takako
T
Kano
Mihoko
M
Yoshimoto
Makoto
M
Towatari
Takae
T
Katunuma
Nobuhiko
N
Shizuka
Fujiko
F
Kishi
Kyoichi
K
D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000097:blood; D056657:Cathepsin K; D002403:Cathepsins / Q000032:analysis / Q000378:metabolism; D017364:Collagenases / Q000032:analysis / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012968:Etidronic Acid / Q000008:administration & dosage / Q000494:pharmacology; D005269:Femur / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D006909:Hydroxyproline / Q000097:blood / Q000378:metabolism; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014893:Weightlessness / Q000009:adverse effects
D015853:Cysteine Proteinase Inhibitors; C034323:EP 459; D002403:Cathepsins; D056657:Cathepsin K; C534133:Ctsk protein, rat; D017364:Collagenases; D007930:Leucine; D012968:Etidronic Acid; D006909:Hydroxyproline; D002118:Calcium