title: Brain-type creatine kinase has a crucial role in osteoclast-mediated bone resorption.
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.
authors: Department of Cell and Developmental Biology, Brain Korea 21, School of Dentistry, Seoul National University, 28 Yeongon-Dong, Jongno-gu, Seoul 110-749, Korea.
authors: Eun-Ju
authors: EJ
authors: Chang
authors: Jeongim
authors: J
authors: Ha
authors: Frank
authors: F
authors: Oerlemans
authors: You Jin
authors: YJ
authors: Lee
authors: Soo Woong
authors: SW
authors: Lee
authors: Jiyoon
authors: J
authors: Ryu
authors: Hyung Joon
authors: HJ
authors: Kim
authors: Youngkyun
authors: Y
authors: Lee
authors: Hyun-Man
authors: HM
authors: Kim
authors: Je-Yong
authors: JY
authors: Choi
authors: Jin Young
authors: JY
authors: Kim
authors: Chan Soo
authors: CS
authors: Shin
authors: Youngmi Kim
authors: YK
authors: Pak
authors: Sakae
authors: S
authors: Tanaka
authors: Bé
authors: B
authors: Wieringa
authors: Zang Hee
authors: ZH
authors: Lee
authors: Hong-Hee
authors: HH
authors: Kim
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001862:Bone Resorption / Q000201:enzymology*; D052276:Creatine Kinase, BB Form / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D015180:Electrophoresis, Gel, Two-Dimensional; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D052276:Creatine Kinase, BB Form