Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos

Koichi Matsuo, Deborah L. Galson, Chen Zhao, Lan Peng, Catherine Laplace, Kent Z Q Wang, Marcus A. Bachler, Hitoshi Amano, Hiroyuki Aburatani, Hiromichi Ishikawa, Erwin F. Wagner

Research output: Contribution to journalArticle

405 Scopus citations

Abstract

Osteoclasts are specialized macrophages that resorb bone. Mice lacking the AP-1 component c-Fos are osteopetrotic because of a lack of osteoclast differentiation and show an increased number of macrophages. The nature of the critical function of c-Fos in osteoclast differentiation is not known. Microarray analysis revealed that Nfatc1, another key regulator of osteoclastogenesis, was down-regulated in Fos-/- osteoclast precursors. Chromatin immunoprecipitation assay showed that c-Fos bound to the Nfatc1 and Acp5 promoters in osteoclasts. In vitro promoter analyses identified nuclear factor of activated T-cells (NFAT)/AP-1 sites in the osteoclast-specific Acp5 and Calcr promoters. Moreover, in Fos-/- precursors gene transfer of an active form of NFAT restored transcription of osteoclast-specific genes in the presence of receptor activator of the NF-κB ligand (RANKL), rescuing bone resorption. In the absence of RANKL, however, Fos-/- precursors were insensitive to NFAT-induced osteoclastogenesis unlike wild-type precursors. These data indicate that lack of Nfatc1 expression is the cause of the differentiation block in Fos-/- osteoclast precursors and that transcriptional induction of Nfatc1 is a major function of c-Fos in osteoclast differentiation.

Original languageEnglish (US)
Pages (from-to)26475-26480
Number of pages6
JournalJournal of Biological Chemistry
Volume279
Issue number25
DOIs
StatePublished - Jun 18 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Matsuo, K., Galson, D. L., Zhao, C., Peng, L., Laplace, C., Wang, K. Z. Q., Bachler, M. A., Amano, H., Aburatani, H., Ishikawa, H., & Wagner, E. F. (2004). Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. Journal of Biological Chemistry, 279(25), 26475-26480. https://doi.org/10.1074/jbc.M313973200