title: The role of TWIST as a regulator in giant cell tumor of bone.
abstract: Giant cell tumor of bone (GCT) is an aggressive tumor consisting of multinucleated osteoclast-like giant cells and proliferating osteoblast-like stromal cells. Our group has reported that the stromal cells express high levels of the bone resorbing matrix metalloproteinase (MMP)-13, and that this expression is regulated by the osteoblast transcription factor Runx2. The purpose of this study was to determine the upstream regulation of Runx2 in GCT cells. Using GCT stromal cells obtained from patient specimens, we demonstrated that TWIST, a master osteogenic regulator, was highly expressed in all GCT specimens. TWIST overexpression downregulated Runx2 expression whereas TWIST siRNA knockdown resulted in Runx2 and MMP-13 upregulation. Interestingly, cells obtained from a GCT lung metastasis showed a reverse regulatory pattern between TWIST and Runx2. In mutational analysis, we revealed a point mutation (R154S) at the Helix2 domain of TWIST. This TWIST mutation may be an essential underlying factor in the development and pathophysiology of these tumors in that they lead to inappropriate TWIST downregulation of Runx2, arrested osteoblastic differentiation, and the maintenance of an immature and neoplastic phenotype.
authors.affiliation: Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Shalini
authors.initials: S
authors.lastname: Singh
authors.forename: Isabella W Y
authors.initials: IW
authors.lastname: Mak
authors.forename: Robert W
authors.initials: RW
authors.lastname: Cowan
authors.forename: Robert
authors.initials: R
authors.lastname: Turcotte
authors.forename: Gurmit
authors.initials: G
authors.lastname: Singh
authors.forename: Michelle
authors.initials: M
authors.lastname: Ghert
mesh_terms: D000595:Amino Acid Sequence; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D015870:Gene Expression; D018212:Giant Cell Tumor of Bone / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D009687:Nuclear Proteins; C493709:RUNX2 protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1