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

Abstract

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.

• Authors: Fumiyo Ikeda, Riko Nishimura, Takuma Matsubara, Sakae Tanaka, Jun-ichiro Inoue, Sakamuri V Reddy, Kenji Hata, Kenji Yamashita, Toru Hiraga, Toshiyuki Watanabe, Toshio Kukita, Katsuji Yoshioka, Anjana Rao, Toshiyuki Yoneda
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 114 Issue 4 Pg. 475-84 (Aug 2004) ISSN: 0021-9738 [Print] United States
• PMID: 15314684 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthracenes
• Carrier Proteins
• DNA-Binding Proteins
• Membrane Glycoproteins
• NFATC Transcription Factors
• Nfatc1 protein, mouse
• Nfatc2 protein, mouse
• Nuclear Proteins
• Proto-Oncogene Proteins c-jun
• RANK Ligand
• Receptor Activator of Nuclear Factor-kappa B
• Tnfrsf11a protein, mouse
• Tnfsf11 protein, mouse
• Transcription Factors
• pyrazolanthrone

Topics

• Adenoviridae (genetics)
• Animals
• Animals, Newborn
• Anthracenes (pharmacology)
• Bone Marrow Cells (cytology, drug effects, metabolism)
• COS Cells
• Carrier Proteins (genetics, metabolism, pharmacology)
• Cell Differentiation
• Cell Line
• Cell Lineage
• Chlorocebus aethiops
• DNA-Binding Proteins (metabolism)
• Enzyme Activation (drug effects)
• Gene Expression Regulation
• Genes, Reporter
• Membrane Glycoproteins (genetics, metabolism, pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Monocytes (cytology, drug effects, metabolism)
• NFATC Transcription Factors
• Nuclear Proteins
• Osteoclasts (drug effects, metabolism, pathology)
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-jun (genetics, metabolism)
• RANK Ligand
• Receptor Activator of Nuclear Factor-kappa B
• Signal Transduction (drug effects)
• Transcription Factors (metabolism)
• Transcriptional Activation