AP-1 as a Regulator of MMP-13 in the Stromal Cell of Giant Cell Tumor of Bone

Isabella W. Y. Mak,Michelle Ghert,Snezana Popovic,Gurmit Singh,Robert E. Turcotte

doi:10.1155/2011/164197

Isabella W. Y. Mak, Michelle Ghert + Show 3 more

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https://doi.org/10.1155/2011/164197

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Abstract

Matrix-metalloproteinase-13 (MMP-13) has been shown to be an important protease in inflammatory and neoplastic conditions of the skeletal system. In particular, the stromal cells of giant cell tumor of bone (GCT) express very high levels of MMP-13 in response to the cytokine-rich environment of the tumor. We have previously shown that MMP-13 expression in these cells is regulated, at least in part, by the RUNX2 transcription factor. In the current study, we identify the expression of the c-Fos and c-Jun elements of the AP-1 transcription factor in these cells by protein screening assays and real-time PCR. We then used siRNA gene knockdown to determine that these elements, in particular c-Jun, are upstream regulators of MMP-13 expression and activity in GCT stromal cells. We conclude that there was no synergy found between RUNX2 and AP-1 in the regulation of the MMP13 expression and that these transcription factors may be independently regulated in these cells.

Highlights

Bone resorption involves dissolution of the nonorganic component of bone, hydroxyapatite, followed by degradation of the collagenous component composed mostly of type-I collagen [1]
To identify which members of the activator protein 1 (AP-1) family are present in giant cell tumor of bone (GCT) stromal cells, an AP-1 screening assay was used to detect specific transcription factor DNA binding activity in the nuclear extracts
MMP-13 has a key role in the MMP activation cascade and appears to be critical in bone metabolism, homeostasis, osteoarthritis, and rheumatoid arthritis [9], but is highly associated with tumor invasion and metastasis [10]

Summary

Introduction

Bone resorption involves dissolution of the nonorganic component of bone, hydroxyapatite, followed by degradation of the collagenous component composed mostly of type-I collagen [1]. Osteoclasts and their ability to create a highly acidic environment are considered necessary for the degradation of hydroxyapatite, the organic components of bone can be degraded at a physiologic pH with varying efficiencies by the type-I collagenases (Matrix metalloproteinases- (MMPs-) 1, -8 and -13) and the gelatinases (MMP-2 and -9) [2, 3]. We have shown that the expression of MMP-13 in the stromal cells is regulated, in part, by the Runx transcription factor [7]

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