Calcium/calmodulin-dependent kinase activity is required for efficient induction of osteoclast differentiation and bone resorption by receptor activator of nuclear factor kappa B ligand (RANKL)
✍ Scribed by Estabelle S.M. Ang; Ping Zhang; James H. Steer; Jamie W.-Y. Tan; Kirk Yip; Ming H. Zheng; David A. Joyce; Jiake Xu
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 521 KB
- Volume
- 212
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Calcium/calmodulin‐dependent protein kinase (CaMK) is a major down stream mediator of Ca^2+^ signaling in a wide range of cellular functions, including ion channel and cell cycle regulation and neurotransmitter synthesis and release. Here we have investigated the role of the CaMK signaling pathway in osteoclast differentiation and bone resorption. We observed that the CaMKI, CaMKII γ isoforms were present in both bone‐marrow derived macrophages and RAW264.7 murine macrophage cell line, and that expression persisted during osteoclast differentiation in the presence of receptor activator of nuclear factor kappa B (NF‐κB) ligand (RANKL). RANKL‐induced differentiation was accompanied by increased cyclic AMP response element transcriptional activity, and ERK phosphorylation, which are both downstream targets of CaMK. Two selective inhibitors of CaMKs, KN‐93 and KN‐62, inhibited osteoclastogenesis in a time and concentration‐dependent manner. This was accompanied by suppression of cathepsin K expression and osteoclastic bone resorption, which are markers for differentiated osteoclast function. KN‐93 and KN‐62 both inhibited RANKL‐induced ERK phosphorylation and CREB transcriptional activity. These findings imply a role for CaMK in osteoclast differentiation and bone resorption. J. Cell. Physiol. 212:787–795, 2007. © 2007 Wiley‐Liss, Inc.