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

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.

Interaction of Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and Vav3 in the Receptor Activator of Nuclear Factor κB (RANK) Signaling Complex Enhances Osteoclastogenesis

“…EEIG1 also shares an IVVY binding motif to form the RANK signaling complex with Gab2 and PLC␥2, although Vav3 recruitment to this signaling complex has not been defined. Interestingly, EEIG1 is involved in RANK-mediated PLC␥2 activation and NFATc1 induction but not NF-B or MAPK activation (28). Thus, the activation of RANK signaling by EEIG1 can be distinguished from TRAF6, Gab2, or Vav3 signaling (19,28).…”

“…Interestingly, EEIG1 is involved in RANK-mediated PLC␥2 activation and NFATc1 induction but not NF-B or MAPK activation (28). Thus, the activation of RANK signaling by EEIG1 can be distinguished from TRAF6, Gab2, or Vav3 signaling (19,28). These previous studies and our current observations emphasize the need for further investigations of KD -BMMs with RANKL (100 ng/ml) and M-CSF (50 ng/ml) for the indicated times and subsequently analyzed via IB with antibodies that recognized phosphorylated or total NFATc1 (7A6), c-Fos (D-1), and CREB (Ser 133 ).…”

“…However, whether Gab2 associates directly with RANK cyto and how Gab2 function is linked to TRAF6 or Vav3 in the RANK signaling complex remain unclear. Choi et al (28) recently identified early estrogen-induced gene 1 (EEIG1) as an another HCR-binding adaptor molecule. EEIG1 also shares an IVVY binding motif to form the RANK signaling complex with Gab2 and PLC␥2, although Vav3 recruitment to this signaling complex has not been defined.…”

Biochemical markers of bone metastasis

“…Так, при наруше-нии продукции OPG развивается остеопороз, а при де-фиците RANKL повышается интенсивность процес-сов костеобразования [10]. Известно, что RANKL связывается со своим рецептором (RANK) на макро-фагах и неактивных остеокластах и вызывает актива-цию и дифференцировку этих клеток, действуя через NF-kβ и N-концевую киназу (JNK) [3,6,11].…”

“…Такие вещества, как ПТГ-подобный протеин (ПТГпП), IL-1, простагландин Е 2 , способны стимулировать активность остеокластов в кост-ной строме -как путем усиления действия RANKL, так и за счет снижения уровня OPG [11]. Примеча-тельно, что воздействие RANKL на некоторые клеточ-ные линии приводит к активации факторов, ответст- венных за миграцию, инвазию и метастазирование.…”