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The role of TWIST as a regulator in giant cell tumor of bone
Author(s) -
Singh Shalini,
Mak Isabella W.Y.,
Cowan Robert W.,
Turcotte Robert,
Singh Gurmit,
Ghert Michelle
Publication year - 2011
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.23149
Subject(s) - runx2 , stromal cell , osteoblast , giant cell tumor of bone , gene knockdown , downregulation and upregulation , cancer research , osteoclast , giant cell , biology , microbiology and biotechnology , regulator , pathology , cell culture , medicine , genetics , gene , in vitro
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.