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.
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.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520; Department of Orthopedics, Shanghai No. 6 People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200233, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yao
authors.affiliation: Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: Gang-Qing
authors.initials: GQ
authors.lastname: Yao
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: Ben-Hua
authors.initials: BH
authors.lastname: Sun
authors.affiliation: Department of Orthopedics, Shanghai No. 6 People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200233, China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Tommasini
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520. Electronic address: karl.insogna@yale.edu.
authors.forename: Karl
authors.initials: K
authors.lastname: Insogna
mesh_terms: D000818:Animals; D001483:Base Sequence; D015519:Bone Density; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000648:ultrastructure; D024202:Electrophoretic Mobility Shift Assay; D016173:Macrophage Colony-Stimulating Factor; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011859:Radiography; D012097:Repressor Proteins / Q000235:genetics*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C491386:Jundp2 protein, mouse; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; C491460:Tbx3 protein, mouse; D016173:Macrophage Colony-Stimulating Factor
keywords: Cytokine; Osteoclast; Promoters; Signal Transduction; Transcription Factors