The role of TWIST as a regulator in giant cell tumor of bone

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 exp...

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Bibliographic Details
Published in:Journal of cellular biochemistry 2011-09, Vol.112 (9), p.2287-2295
Main Authors: Singh, Shalini, Mak, Isabella W.Y., Cowan, Robert W., Turcotte, Robert, Singh, Gurmit, Ghert, Michelle
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Bone matrix
Bone Neoplasms - metabolism
Bone Neoplasms - pathology
Bone tumors
Cbfa-1 protein
Collagenase 3
Core Binding Factor Alpha 1 Subunit - genetics
Core Binding Factor Alpha 1 Subunit - metabolism
Differentiation
DNA Mutational Analysis
Down-Regulation
Gene Expression
Giant cell tumor
Giant Cell Tumor of Bone - metabolism
Giant Cell Tumor of Bone - pathology
Giant cells
Humans
Lung
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Lung Neoplasms - secondary
Matrix metalloproteinase
Metastases
Molecular Sequence Data
Mutation, Missense
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Osteoblastogenesis
Osteoblasts
Point mutation
Primary cell culture
Protein Transport
Runx2
siRNA
stromal cells
Stromal Cells - metabolism
Stromal Cells - pathology
Transcription factors
Transfection
Tumor Cells, Cultured
Tumors
TWIST
Twist-Related Protein 1 - genetics
Twist-Related Protein 1 - metabolism
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Summary: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. J. Cell. Biochem. 112: 2287–2295, 2011. © 2011 Wiley‐Liss, Inc.
ISSN:0730-2312
1097-4644
1097-4644
DOI:10.1002/jcb.23149