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Regulation of osteoclast differentiation and function by the CaMK-CREB pathway

Academic Article
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Overview

authors

  • Sato, K.
  • Suematsu, A.
  • Nakashima, T.
  • Takemoto-Kimura, S.
  • Aoki, K.
  • Morishita, Y.
  • Asahara, Hiroshi
  • Ohya, K.
  • Yamaguchi, A.
  • Takai, T.
  • Kodama, T.
  • Chatila, T. A.
  • Bito, H.
  • Takayanagi, H.

publication date

  • December 2006

journal

  • Nature Medicine  Journal

abstract

  • Calcium (Ca(2+)) signaling is essential for a variety of cellular responses and higher biological functions. Ca(2+)/calmodulin-dependent kinases (CaMKs) and the phosphatase calcineurin activate distinct downstream pathways that are mediated by the transcription factors cAMP response element (CRE)-binding protein (CREB) and nuclear factor of activated T cells (NFAT), respectively. The importance of the calcineurin-NFAT pathway in bone metabolism has been demonstrated in osteoclasts, osteoblasts and chondrocytes. However, the contribution of the CaMK-CREB pathway is poorly understood, partly because of the difficulty of dissecting the functions of homologous family members. Here we show that the CaMKIV-CREB pathway is crucial for osteoclast differentiation and function. Pharmacological inhibition of CaMKs as well as the genetic ablation of Camk4 reduced CREB phosphorylation and downregulated the expression of c-Fos, which is required for the induction of NFATc1 (the master transcription factor for osteoclastogenesis) that is activated by receptor activator of NF-kappaB ligand (RANKL). Furthermore, CREB together with NFATc1 induced the expression of specific genes expressed by differentiated osteoclasts. Thus, the CaMK-CREB pathway biphasically functions to regulate the transcriptional program of osteoclastic bone resorption, by not only enhancing induction of NFATc1 but also facilitating NFATc1-dependent gene regulation once its expression is induced. This provides a molecular basis for a new therapeutic strategy for bone diseases.

subject areas

  • Animals
  • Bone Resorption
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cell Differentiation
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Molecular Sequence Data
  • NFATC Transcription Factors
  • Osteoclasts
  • Phosphorylation
  • Proto-Oncogene Proteins c-fos
  • RANK Ligand
  • Signal Transduction
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Identity

International Standard Serial Number (ISSN)

  • 1078-8956

Digital Object Identifier (DOI)

  • 10.1038/nm1515

PubMed ID

  • 17128269
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Additional Document Info

start page

  • 1410

end page

  • 1416

volume

  • 12

issue

  • 12

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