RRC ID 29216
Author Yao C, Yao GQ, Sun BH, Zhang C, Tommasini SM, Insogna K.
Title The transcription factor T-box 3 regulates colony-stimulating factor 1-dependent Jun dimerization protein 2 expression and plays an important role in osteoclastogenesis.
Journal J Biol Chem
Abstract Colony-stimulating factor 1 (CSF1) is known to promote osteoclast progenitor survival, but its roles in osteoclast differentiation and mature osteoclast function are less well understood. In a microarray screen, Jun dimerization protein 2 (JDP2) was identified as significantly induced by CSF1. Recent reports indicate that JDP2 is required for normal osteoclastogenesis and skeletal metabolism. Because there are no reports on the transcriptional regulation of this gene, the DNA sequence from -2612 to +682 bp (relative to the transcription start site) of the JDP2 gene was cloned, and promoter activity was analyzed. The T box-binding element (TBE) between -191 and -141 bp was identified as the cis-element responsible for CSF1-dependent JDP2 expression. Using degenerate PCR, Tbx3 was identified as the major isoform binding the TBE. Overexpression of Tbx3 induced JDP2 promoter activity, whereas suppressing Tbx3 expression substantially attenuated CSF1-induced transcription. Suppressing Tbx3 in osteoclast precursors reduced JDP2 expression and significantly impaired RANKL/CSF1-induced osteoclastogenesis. A MEK1/2-specific inhibitor was found to block CSF1-induced JDP2 expression. Consistent with these data, JDP2(-/-) mice were found to have increased bone mass. In summary, CSF1 up-regulates JDP2 expression by inducing Tbx3 binding to the JDP2 promoter. The downstream signaling cascade from activated c-Fms involves the MEK1/2-ERK1/2 pathway. Tbx3 plays an important role in osteoclastogenesis at least in part by regulating CSF1-dependent expression of JDP2.
Volume 289(10)
Pages 6775-6790
Published 2014-3-7
DOI 10.1074/jbc.M113.499210
PII S0021-9258(20)44495-3
PMID 24394418
PMC PMC3945339
MeSH Animals Base Sequence Bone Density Bone and Bones / diagnostic imaging Bone and Bones / ultrastructure Electrophoretic Mobility Shift Assay Macrophage Colony-Stimulating Factor Mice Mice, Knockout Molecular Sequence Data Osteoclasts / cytology Osteoclasts / metabolism Osteoclasts / physiology* Promoter Regions, Genetic Radiography Repressor Proteins / genetics* T-Box Domain Proteins / genetics T-Box Domain Proteins / metabolism* Transcriptional Activation*
IF 4.238
Times Cited 8
Mice RBRC02392