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Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation.

Authors: Ikeda, F  Nishimura, R  Matsubara, T  Tanaka, S  Inoue, J  Reddy, SV  Hata, K  Yamashita, K  Hiraga, T  Watanabe, T  Kukita, T  Yoshioka, K  Rao, A  Yoneda, T 
Citation: Ikeda F, etal., J Clin Invest 2004 Aug;114(4):475-84.
Pubmed: (View Article at PubMed) PMID:15314684
DOI: Full-text: DOI:10.1172/JCI19657

Receptor activator of NF-kappaB ligand (RANKL) plays an essential role in osteoclast formation and bone resorption. Although genetic and biochemical studies indicate that RANKL regulates osteoclast differentiation by activating receptor activator of NF-kappaB and associated signaling molecules, the molecular mechanisms of RANKL-regulated osteoclast differentiation have not yet been fully established. We investigated the role of the transcription factor c-Jun, which is activated by RANKL, in osteoclastogenesis using transgenic mice expressing dominant-negative c-Jun specifically in the osteoclast lineage. We found that the transgenic mice manifested severe osteopetrosis due to impaired osteoclastogenesis. Blockade of c-Jun signaling also markedly inhibited soluble RANKL-induced osteoclast differentiation in vitro. Overexpression of nuclear factor of activated T cells 1 (NFAT1) (NFATc2/NFATp) or NFAT2 (NFATc1/NFATc) promoted differentiation of osteoclast precursor cells into tartrate-resistant acid phosphatase-positive (TRAP-positive) multinucleated osteoclast-like cells even in the absence of RANKL. Overexpression of NFAT1 also markedly transactivated the TRAP gene promoter. These osteoclastogenic activities of NFAT were abrogated by overexpression of dominant-negative c-Jun. Importantly, osteoclast differentiation and induction of NFAT2 expression by NFAT1 overexpression or soluble RANKL treatment were profoundly diminished in spleen cells of the transgenic mice. Collectively, these results indicate that c-Jun signaling in cooperation with NFAT is crucial for RANKL-regulated osteoclast differentiation.

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CRRD Object Information
CRRD ID: 1549450
Created: 2005-08-29
Species: All species
Last Modified: 2005-08-29
Status: ACTIVE



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