Abstract
NF-κB is one of the key transcription factors activated by receptor activator of NF-κB ligand (RANKL) during osteoclast differentiation. The 8-kDa dynein L chain (LC8) was previously identified as a novel NF-κB regulator. However, its physiological role as an NF-κB inhibitor remains elusive. In this study, we showed the inhibitory role of LC8 in RANKL-induced osteoclastogenesis and signaling pathways and its protective role in osteolytic animal models. LC8 suppressed RANKL-induced osteoclast differentiation, actin ring formation, and osteoclastic bone resorption. LC8 inhibited RANKL-induced phosphorylation and subsequent degradation of IκBα, the expression of c-Fos, and the consequent activation of NFATc1, which is a pivotal determinant of osteoclastogenesis. LC8 also inhibited RANKL-induced activation of JNK and ERK. LC8-transgenic mice exhibited a mild osteopetrotic phenotype. Moreover, LC8 inhibited inflammation-induced bone erosion and protected against ovariectomy-induced bone loss in mice. Thus, our results suggest that LC8 inhibits osteoclast differentiation by regulating NF-κB and MAPK pathways and provide the molecular basis of a new strategy for treating osteoporosis and other bone diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / analysis
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Animals
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Bone Resorption / prevention & control*
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Cell Differentiation
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Cytoplasmic Dyneins / genetics
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Cytoplasmic Dyneins / physiology*
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Cytoplasmic Dyneins / toxicity
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Drug Evaluation, Preclinical
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Enzyme Activation
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Gene Expression Regulation / physiology
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Genes, fos
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Humans
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I-kappa B Proteins / metabolism
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MAP Kinase Signaling System / physiology
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Macrophages / cytology
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Macrophages / drug effects
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism
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NFATC Transcription Factors / biosynthesis
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NFATC Transcription Factors / genetics
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Osteoclasts / pathology*
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Osteolysis / physiopathology
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Osteolysis / prevention & control*
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Osteopetrosis / genetics
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Osteoporosis, Postmenopausal / physiopathology
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Osteoporosis, Postmenopausal / prevention & control
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Phosphorylation
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Protein Processing, Post-Translational
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Proto-Oncogene Proteins c-fos / biosynthesis
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RANK Ligand / antagonists & inhibitors*
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Recombinant Fusion Proteins / physiology
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Recombinant Fusion Proteins / toxicity
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Signal Transduction / physiology*
Substances
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Actins
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I-kappa B Proteins
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NF-kappa B
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NFATC Transcription Factors
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NFKBIA protein, human
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Nfatc1 protein, mouse
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Nfkbia protein, mouse
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Proto-Oncogene Proteins c-fos
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RANK Ligand
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Recombinant Fusion Proteins
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Tnfsf11 protein, mouse
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NF-KappaB Inhibitor alpha
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DYNLL1 protein, human
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Cytoplasmic Dyneins