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A more recent version of this article appeared on October 21, 2005
Papers In Press, published online ahead of print August 18, 2005
J. Biol. Chem, 10.1074/jbc.M505815200
Submitted on May 27, 2005
Revised on August 18, 2005
Accepted on August 18, 2005
NFATc1 induces OSCAR gene expression during TRANCE-mediated osteoclastogenesis
Kabsun Kim, Jung Ha Kim, Junwon Lee, Hye-Mi Jin, Seoung-Hoon Lee, David E. Fisher, Hyun Kook, Kyung Keun Kim, Yongwon Choi, and Nacksung Kim
Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746
Corresponding Author: nacksung{at}jnu.ac.kr or nacksungkim@hotmail.com
Osteoclast differentiation from hematopoietic precursors is controlled by the TNF family member TRANCE via induction of various transcription factors, including nuclear factor of activated T cells (NFAT) c1. During osteoclast differentiation, NFATc1 is further activated via calcium signaling when costimulatory receptors expressed on osteoclast precursors, such as osteoclast-associated receptor (OSCAR), are stimulated. Here we show that NFATc1 expression precedes that of OSCAR during TRANCE-mediated osteoclastogenesis, and that inhibition of NFATc1 by cyclosporin A abolishes TRANCE-induced OSCAR expression and subsequent osteoclast differentiation. Moreover, we show that the 1.0-Kb promoter region of the OSCAR gene contains three potential NFATc1-binding sites. Induction of an OSCAR promoter-luciferase reporter is significantly increased when transiently transfected into 293T cells in combination with NFATc1 expression plasmid. Deletion and site-directed mutant constructs confirmed that NFATc1-binding sites are both functional and NFATc1-specific. Furthermore, NFATc1 synergistically activates an OSCAR reporter construct together with microphthalmia transcription factor (Mitf) and PU.1, transcription factors previously shown to be critical for osteoclast differentiation. In addition, a plasmid expressing constitutively active MKK6 enhances the transactivation activity of NFATc1/Mitf/PU.1 on the OSCAR promoter. Taken together, our results indicate that NFATc1 is an important transcription factor in the induction of OSCAR during osteoclastogenesis. Elucidation of NFATc1 as a transcription factor for OSCAR expression implies the presence of a positive feedback circuit of TRANCE-induced activation of NFATc1, involving NFATc1-mediated OSCAR expression, and its subsequent activation of NFATc1, necessary for efficient differentiation of osteoclasts.

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Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.
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