Id helix-loop-helix proteins negatively regulate TRANCE-mediated osteoclast differentiation.
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.
Lee
Junwon
J
Medical Research Center for Gene Regulation, Chonnam National University Medical School, Hak-Dong 5, Dong-Ku, Gwangju 501-746, Korea.
Kim
Kabsun
K
Kim
Jung Ha
JH
Jin
Hye Mi
HM
Choi
Han Kyung
HK
Lee
Seoung-Hoon
SH
Kook
Hyun
H
Kim
Kyung Keun
KK
Yokota
Yoshifumi
Y
Lee
Soo Young
SY
Choi
Yongwon
Y
Kim
Nacksung
N
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
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