title: TIEG1 enhances Osterix expression and mediates its induction by TGFβ and BMP2 in osteoblasts.
abstract: Deletion of TIEG1/KLF10 in mice results in an osteopenic skeletal phenotype with significant decreases in both bone mineral density and content throughout the skeleton. Calvarial osteoblasts isolated from TIEG1 knockout (KO) mice display numerous changes in gene expression and exhibit significant delays in their mineralization rates relative to wild-type (WT) controls. Here, we demonstrate that loss of TIEG1 expression in osteoblasts results in decreased levels of Osterix mRNA. Suppression of TIEG1 expression in WT osteoblasts leads to decreased Osterix expression while restoration of TIEG1 expression in TIEG1 KO osteoblasts results in increased levels of Osterix. Transient transfection and chromatin immunoprecipitation assays reveal that TIEG1 directly binds to and activates the Osterix promoter and demonstrate that the zinc finger-containing DNA binding domain of TIEG1 is necessary for this regulation. Furthermore, we reveal that TIEG1 expression is essential for the induction of Osterix expression by important bone-related cytokines such as TGFβ and BMP2 in osteoblast cells. Taken together, these data implicate an important role for TIEG1 in regulating the expression of Osterix, a master regulator of osteoblast differentiation and bone formation, and suggest that decreased expression of Osterix, as well as impaired TGFβ and BMP2 signaling, contribute to the observed osteopenic bone phenotype of TIEG1 KO mice.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Malayannan
authors.initials: M
authors.lastname: Subramaniam
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Pitel
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Withers
authors.affiliation: Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, UConn Health, Farmington, CT 06030, USA.
authors.forename: Hicham
authors.initials: H
authors.lastname: Drissi
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: hawse.john@mayo.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Hawse
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000378:metabolism* / Q000473:pathology; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors
chemical_list: D055396:Bone Morphogenetic Protein 2; D004268:DNA-Binding Proteins; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C525719:Bmp2 protein, mouse; C479466:Sp7 protein, mouse; C569958:KLF10 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors
keywords: BMP2; KLF10; Osteoblast; Osterix; TGFβ; TIEG1