Abstract
The receptor activator of NF-κB (RANK) and immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors are essential factors involved in regulating osteoclast formation and bone remodeling. Here, we identify early estrogen-induced gene 1 (EEIG1) as a novel RANK ligand (RANKL)-inducible protein that physically interacts with RANK and further associates with Gab2, PLCγ2 and Tec/Btk kinases upon RANKL stimulation. EEIG1 positively regulates RANKL-induced osteoclast formation, likely due to its ability to facilitate RANKL-stimulated PLCγ2 phosphorylation and NFATc1 induction. In addition, an inhibitory peptide designed to block RANK-EEIG1 interaction inhibited RANKL-induced bone destruction by reducing osteoclast formation. Together, our results identify EEIG1 as a novel RANK signaling component controlling RANK-mediated osteoclast formation, and suggest that targeting EEIG1 might represent a new therapeutic strategy for the treatment of pathological bone resorption.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Bone Marrow Cells / cytology
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / metabolism*
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Bone Resorption / genetics
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Bone Resorption / metabolism
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Bone Resorption / pathology
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Cell Differentiation
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Cell Line
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Gene Expression Regulation / drug effects
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Humans
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Mice
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NFATC Transcription Factors / genetics
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NFATC Transcription Factors / metabolism
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Osteoclasts / cytology
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Osteoclasts / drug effects
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Osteoclasts / metabolism*
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Peptides / pharmacology
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Phospholipase C gamma / genetics
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Phospholipase C gamma / metabolism
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Phosphorylation / drug effects
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Protein Binding
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Proteins
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RANK Ligand / genetics*
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RANK Ligand / metabolism
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Receptor Activator of Nuclear Factor-kappa B / antagonists & inhibitors
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Receptor Activator of Nuclear Factor-kappa B / genetics*
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Receptor Activator of Nuclear Factor-kappa B / metabolism
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Signal Transduction / drug effects
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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FAM102A protein, human
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GAB2 protein, human
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NFATC Transcription Factors
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NFATC1 protein, human
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Peptides
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Proteins
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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TNFRSF11A protein, human
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TNFSF11 protein, human
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Tec protein-tyrosine kinase
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Protein-Tyrosine Kinases
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Phospholipase C gamma