Changes in micro-CT 3D bone parameters reflect effects of a potent cathepsin K inhibitor (SB-553484) on bone resorption and cortical bone formation in ovariectomized mice.

Changes in micro-CT 3D bone parameters reflect effects of a potent cathepsin K inhibitor (SB-553484) on bone resorption and cortical bone formation in ovariectomized mice. Research Abstract Details 

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Changes in micro-CT 3D bone parameters reflect effects of a potent cathepsin K inhibitor (SB-553484) on bone resorption and cortical bone formation in ovariectomized mice. Abstract Text:

Anbo Xiang,Masahiro Kanematsu,Sanjay Kumar,Dennis Yamashita,Toshihiko Kaise,Hideo Kikkawa,Satoshi Asano,Mine Kinoshita,Anbo Xiang,Masahiro Kanematsu,Sanjay Kumar,Dennis Yamashita,Toshihiko Kaise,Hideo Kikkawa,Satoshi Asano,Mine Kinoshita,

Cathepsin K is a cysteine proteinase that is highly expressed by osteoclasts and is being pursued as a potential drug target for the treatment of osteoporosis. We have reported that microcomputed tomography (micro-CT) analysis of bone microarchitecture may serve as a valuable tool for evaluating both antiresorptive and anabolic agents in ovariectomized (OVX) mice. The purpose of this study was to evaluate the effect of SB-553484, a novel cathepsin K inhibitor (human Ki,app=0.14 nM, mouse Ki,app=26 nM), on the OVX mice by micro-CT bone morphometric analysis. Seven weeks female BALB/c mice were OVX or sham-operated. OVX animals were treated with SB-553484 (30 mg/kg, sc) or Rolipram (10 mg/kg, po), a phosphodiesterase 4 inhibitor used as a positive bone anabolic agent, twice a day for 2 weeks. Both SB-553484 and Rolipram significantly prevented the decrease of trabecular bone volume as well as the deterioration of trabecular architecture in OVX mice. Interestingly, SB-553484 demonstrated a more pronounced effect in improvement of trabecular separation, number and connectivity, and a weaker effect in improvement of trabecular thickness compared to that of Rolipram. These differences indicate that SB-553484 mainly acted as an antiresorptive agent in OVX-induced loss of trabecular bone. On the other hand, SB-553484 significantly increased cortical bone volume and cortical thickness as well as Rolipram in OVX mice indicating an unexpected stimulatory effect of SB-553484 on cortical bone formation. These data suggest that targeting cathepsin K may prove therapeutically beneficial in the treatment of diseases with accelerated bone loss such as postmenopausal osteoporosis not only by inhibiting bone resorption but also by potentially stimulating cortical bone formation.

Changes in micro-CT 3D bone parameters reflect effects of a potent cathepsin K inhibitor (SB-553484) on bone resorption and cortical bone formation in ovariectomized mice. Publishing Authors By Initials

A Xiang,M Kanematsu,S Kumar,D Yamashita,T Kaise,H Kikkawa,S Asano,M Kinoshita,A Xiang,M Kanematsu,S Kumar,D Yamashita,T Kaise,H Kikkawa,S Asano,M Kinoshita,

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Changes in micro-CT 3D bone parameters reflect effects of a potent cathepsin K inhibitor (SB-553484) on bone resorption and cortical bone formation in ovariectomized mice. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Bone

VOLUME: 40

Page Numbers: 1231-7

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ISSN: 8756-3282

DAY: 24

MONTH: 01

YEAR: 2007

Changes in micro-CT 3D bone parameters reflect effects of a potent cathepsin K inhibitor (SB-553484) on bone resorption and cortical bone formation in ovariectomized mice. Information

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LANGUAGE: eng

NlmUniqueID: 8504048

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Grant and Affiliation Information for Changes in micro-CT 3D bone parameters reflect effects of a potent cathepsin K inhibitor (SB-553484) on bone resorption and cortical bone formation in ovariectomized mice.

AFFILIATION: Department of Pharmacology, Tsukuba Research Laboratories, GlaxoSmithKline K.K., 43 Wadai, Tsukuba, Ibaraki 300-4247, Japan.

Country: United States

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MEDLINETA: Bone

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