title: Early growth response 2 negatively modulates osteoclast differentiation through upregulation of Id helix-loop-helix proteins.
abstract: Early growth response 2 (Egr2) is a zinc finger transcription factor that acts as an important modulator of various physiological processes. In this study, we show that Egr2 negatively regulates receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation. The overexpression of Egr2 in bone marrow-derived macrophages (BMMs) suppresses the formation of multinuclear osteoclasts and the expression of osteoclastogenic markers, including nuclear factor of activated T cells c1 (NFATc1). On the other hand, Egr2 overexpression does not impact the phagocytic activity of osteoclast precursors or the expression of macrophage-specific markers in the presence of the osteoclastogenic stimuli, RANKL and M-CSF. We further demonstrate that Egr2 induces the expression of the inhibitors of differentiation/DNA binding (Ids) helix-loop-helix (HLH) transcription factors, which are important repressors in RANKL-mediated osteoclastogenesis. Egr2 transactivates the Id2 promoter and increases its recruitment to the Id2 promoter region. In addition, Egr2-dependent induction of Id2 promoter activity, and its binding to the Id2 promoter is abrogated by the overexpression of the Egr2 repressor, NGFI-A binding protein 2 (Nab2). Accordingly, coexpression with Nab2 restores Egr2-mediated suppression of osteoclast differentiation. Furthermore, knockdown of Egr2 using shRNA enhances osteoclastogenesis and decreases Id2 gene expression. Ectopic expression of Id2 reverses the phenotype mediated by Egr2 silencing. Taken together, our results identify Egr2 as an important modulator of RANKL-induced osteoclast differentiation and provide the link between RANKL, Egr2 and Id proteins in osteoclast-lineage cells.
authors: Skeletal Diseases Genome Research Center, Kyungpook National University and Hospital, Daegu 700-412, Republic of Korea. biohjk@hanmail.net
authors: Hyun-Ju
authors: HJ
authors: Kim
authors: Jung Min
authors: JM
authors: Hong
authors: Kyung-Ae
authors: KA
authors: Yoon
authors: Nacksung
authors: N
authors: Kim
authors: Dong-Woo
authors: DW
authors: Cho
authors: Je-Yong
authors: JY
authors: Choi
authors: In-Kyu
authors: IK
authors: Lee
authors: Shin-Yoon
authors: SY
authors: Kim
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D051767:Early Growth Response Protein 2 / Q000502:physiology*; D018257:Helix-Loop-Helix Motifs; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology*; D010587:Phagocytosis; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse