title: Id helix-loop-helix proteins negatively regulate TRANCE-mediated osteoclast differentiation.
abstract: Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) induces osteoclast formation from monocyte/macrophage lineage cells via various transcription factors, including the Mi transcription factor (Mitf). Here, we show that inhibitors of differentiation/DNA binding (Ids), helix-loop-helix (HLH) transcription factors, negatively regulate TRANCE-induced osteoclast differentiation. Expression levels of Id1, Id2, and Id3 genes are significantly reduced by TRANCE during osteoclastogenesis. Interestingly, overexpression of the 3 Id genes in bone marrow-derived monocyte/macrophage lineage cells (BMMs) inhibits the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts, but it does not alter the ability of BMMs to either phagocytose or differentiate into dendritic cells (DCs). Overexpression of Id2 in BMMs attenuates the gene induction of nuclear factor of activated T cells c1 (NFATc1) and osteoclast-associated receptor (OSCAR) during TRANCE-mediated osteoclastogenesis. Furthermore, Id proteins interact with Mitf, a basic HLH (bHLH) transcription factor, and inhibit its transactivation of OSCAR, which is a costimulatory receptor expressed by osteoclast precursors, by attenuating the DNA binding ability of Mitf to the E-box site of the OSCAR promoter. Taken together, our results reveal both a new facet of negative regulation, mediated by Id proteins, as well as the mechanism whereby TRANCE signaling overcomes it, allowing osteoclastogenesis to proceed.
authors.affiliation: Medical Research Center for Gene Regulation, Chonnam National University Medical School, Hak-Dong 5, Dong-Ku, Gwangju 501-746, Korea.
authors.forename: Junwon
authors.initials: J
authors.lastname: Lee
authors.forename: Kabsun
authors.initials: K
authors.lastname: Kim
authors.forename: Jung Ha
authors.initials: JH
authors.lastname: Kim
authors.forename: Hye Mi
authors.initials: HM
authors.lastname: Jin
authors.forename: Han Kyung
authors.initials: HK
authors.lastname: Choi
authors.forename: Seoung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Hyun
authors.initials: H
authors.lastname: Kook
authors.forename: Kyung Keun
authors.initials: KK
authors.lastname: Kim
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Yokota
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Nacksung
authors.initials: N
authors.lastname: Kim
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000502:physiology*; D017931:DNA Primers; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000502:physiology; D010587:Phagocytosis; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; C497455:Idb1 protein, mouse; C497452:Idb2 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; C067679:Idb3 protein, mouse