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

Eun Ju Chang, Jeongim Ha, Frank Oerlemans, You Jin Lee, Soo Woong Lee, Jiyoon Ryu, Hyung Joon Kim, Youngkyun Lee, Hyun Man Kim, Je Yong Choi, Jin Young Kim, Chan Soo Shin, Youngmi Kim Pak, Sakae Tanaka, Bé Wieringa, Zang Hee Lee, Hong Hee Kim

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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-κB 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.

Original languageEnglish (US)
Pages (from-to)966-972
Number of pages7
JournalNature Medicine
Volume14
Issue number9
DOIs
StatePublished - Sep 2008
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'Brain-type creatine kinase has a crucial role in osteoclast-mediated bone resorption'. Together they form a unique fingerprint.

Cite this