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

Kojiro Sato, Ayako Suematsu, Tomoki Nakashima, Sayaka Takemoto-Kimura, Kazuhiro Aoki, Yasuyuki Morishita, Hiroshi Asahara, Keiichi Ohya, Akira Yamaguchi, Toshiyuki Takai, Tatsuhiko Kodama, Talal A. Chatila, Haruhiko Bito, Hiroshi Takayanagi

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226 Citations (Scopus)

Abstract

Calcium (Ca2+) signaling is essential for a variety of cellular responses and higher biological functions. Ca2+/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-κB 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.

Original languageEnglish
Pages (from-to)1410-1416
Number of pages7
JournalNature Medicine
Volume12
Issue number12
DOIs
Publication statusPublished - 2006 Dec 1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Sato, K., Suematsu, A., Nakashima, T., Takemoto-Kimura, S., Aoki, K., Morishita, Y., Asahara, H., Ohya, K., Yamaguchi, A., Takai, T., Kodama, T., Chatila, T. A., Bito, H., & Takayanagi, H. (2006). Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nature Medicine, 12(12), 1410-1416. https://doi.org/10.1038/nm1515