Early estrogen-induced gene 1, a novel RANK signaling component, is essential for osteoclastogenesis

The receptor activator of NF-KB （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 inter- acts with RANK and further associates with Gab2, PLC3,2 and Tee/Btk kinases upon RANKL stimulation. EEIG1 positively regulates RANKL-induced osteoclast formation, likely due to its ability to facilitate RANKL-stimulated PLCv2 phosphorylation and NFATcl 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.