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Brain-type creatine kinase has a crucial role in osteoclast-mediated bone resorption

Cited 70 time in Web of Science Cited 71 time in Scopus
Authors
Chang, Eun-Ju; Ha, Jeongim; Oerlemans, Frank; Lee, You Jin; Lee, Soo Woong; Ryu, Jiyoon; Kim, Hyung Joon; Lee, Youngkyun; Kim, Hyun-Man; Choi, Je-Yong; Kim, Jin Young; Shin, Chan Soo; Pak, Youngmi Kim; Tanaka, Sakae; Wieringa, Be; Lee, Zang Hee; Kim, Hong-Hee
Issue Date
2008-08-30
Publisher
Nature Publishing Group
Citation
Nat Med. 2008 Sep;14(9):966-72.
Keywords
AnimalsBlotting, WesternBone Resorption/*enzymologyCreatine Kinase, BB Form/genetics/*metabolismDNA Primers/geneticsElectrophoresis, Gel, Two-DimensionalMiceMice, Inbred ICRMice, KnockoutOsteoclasts/*metabolismRNA InterferenceReverse Transcriptase Polymerase Chain Reaction
Abstract
Osteoclasts differentiate from precursor cells of the monocyte-macrophage lineage and subsequently become activated to be competent for bone resorption through programs primarily governed by receptor activator of nuclear factor-kappaB ligand in cooperation with macrophage colony-stimulating factor. Proteins prominently expressed at late phases of osteoclastogenesis and with a supportive role in osteoclast function are potential therapeutic targets for bone-remodeling disorders. In this study, we used a proteomics approach to show that abundance of the brain-type cytoplasmic creatine kinase (Ckb) is greatly increased during osteoclastogenesis. Decreasing Ckb abundance by RNA interference or blocking its enzymatic activity with a pharmacological inhibitor, cyclocreatine, suppressed the bone-resorbing activity of osteoclasts grown in vitro via combined effects on actin ring formation, RhoA GTPase activity and vacuolar ATPase function. Activities of osteoclasts derived from Ckb-/- mice were similarly affected. In vivo studies showed that Ckb-/- mice were better protected against bone loss induced by ovariectomy, lipopolysaccharide challenge or interleukin-1 treatment than wild-type controls. Furthermore, administration of cyclocreatine or adenoviruses harboring Ckb small hairpin RNA attenuated bone loss in rat and mouse models. Our findings establish an important role for Ckb in the bone-resorbing function of osteoclasts and underscore its potential as a new molecular target for antiresorptive drug development.
ISSN
1546-170X (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18724377

http://www.nature.com/nm/journal/v14/n9/pdf/nm.1860.pdf

http://hdl.handle.net/10371/63092
DOI
https://doi.org/10.1038/nm.1860
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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