RRC ID 1377
Author 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.
Title Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation.
Journal J Clin Invest
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.
Volume 114(4)
Pages 475-84
Published 2004-8
DOI 10.1172/JCI19657
PMID 15314684
PMC PMC503767
MeSH Adenoviridae / genetics Animals Animals, Newborn Anthracenes / pharmacology Bone Marrow Cells / cytology Bone Marrow Cells / drug effects Bone Marrow Cells / metabolism COS Cells Carrier Proteins / genetics Carrier Proteins / metabolism* Carrier Proteins / 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 Membrane Glycoproteins / metabolism* Membrane Glycoproteins / pharmacology Mice Mice, Inbred C57BL Mice, Transgenic Monocytes / cytology Monocytes / drug effects Monocytes / metabolism NFATC Transcription Factors Nuclear Proteins* Osteoclasts / drug effects Osteoclasts / metabolism* Osteoclasts / pathology Promoter Regions, Genetic Proto-Oncogene Proteins c-jun / genetics Proto-Oncogene Proteins c-jun / metabolism* RANK Ligand Receptor Activator of Nuclear Factor-kappa B Signal Transduction / drug effects* Transcription Factors / metabolism* Transcriptional Activation
IF 12.282
Times Cited 344
DNA material pBS rcjun-1 Rat c-Jun protooncogene (RDB1130)
Human and Animal Cells RAW 264(RCB0535) COS-7(RCB0539)