Evidence for the role of matrix metalloproteinase-13 in bone resorption by giant cell tumor of bone

McMaster University, Hamilton, Ontario, Canada L8V 5C2.
Human pathology (Impact Factor: 2.81). 09/2010; 41(9):1320-9. DOI: 10.1016/j.humpath.2010.03.001
Source: PubMed

ABSTRACT Giant cell tumor of bone (GCT) is an aggressively osteolytic primary bone tumor that is characterized by the presence of abundant multinucleated osteoclast-like giant cells, hematopoietic monocytes, and a distinct mesenchymal stromal cell component. Previous work in our laboratory has shown that matrix metalloproteinase (MMP)-13 is the principal proteinase expressed by the stromal cells of GCT. The release of cytokines, particularly interleukin-1beta, by the giant cells of GCT acts on stromal cells to stimulate a surge in MMP-13 secretion. The purpose of this study was to determine the bone resorption capabilities of the cellular elements of GCT and the significance of the MMP-13 expression involved in GCT bone resorption. We present a 3-dimensional histomorphometric technique developed to analyze resorption pit depth and yield an accurate measurement of bone resorption with a direct physical view of lacunae on bone slices. In this study, we demonstrate that the mesenchymal stromal cells and the multinucleated giant cells of GCT are independently capable of bone resorption. However, coculture of these 2 cell fractions shows a synergistic increase in bone resorption. In addition, inhibition of MMP-13 reduces resorptive activity of the cells indicating that MMP-13 likely plays an important role in this tumor. This cell-cell cooperation involves giant cell-derived cytokine up-regulation of MMP-13 in the stromal cells, which in turn assists the giant cells in bone resorption. Future research will involve elucidation of the role of cell-cell/matrix communication pathways in bone resorption and tumorigenesis in GCT.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Giant cell tumor (GCT) of bone is an aggressive skeletal tumor characterized by localized bone resorption. Matrix metalloproteinase-13 (MMP-13) is the principal proteinase expressed by the stromal cells of GCT (GCTSCs) and also considered to play a crucial role in formation of the osteolytic lesion in GCT. The exact mechanism of the regulation of MMP-13 expression in GCTSCs was unknown. In this study, we identified miR-126-5p was significantly downregulated in GCTSCs and affect osteoclast (OC) differentiation and bone resorption by repressing MMP-13 expression at the post-transcriptional level. Thus, our studies show that miR-126-5p plays an important physiological role in giant cell formation and osteolytic lesion in GCT.
    Biochemical and Biophysical Research Communications 12/2013; 443(3). DOI:10.1016/j.bbrc.2013.12.075 · 2.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract The nature of the mononuclear stromal cells (MSCs) in giant cell tumor of bone (GCTB) has not been thoroughly investigated. The purpose of this study was to evaluate the degree and significance of myofibroblastic differentiation in 18 cases of GCTB by immunohistochemistry (IH) and/or electron microscopy (EM). All immunostained cases were found positive for smooth muscle actin (SMA) and/or muscle specific actin (MSA), most in 1-33% of the MSCs. Ultrastructurally, most MSCs were fibroblasts, and a significant number of cells displayed myofibroblastic differentiation. Myofibroblasts are an important component of MSCs in GCTB. The myofibroblastic population may be responsible in part for the production of matrix metalloproteinases (MMPs), which probably play a role in bone destruction, tumor aggression, and recurrence.
    Ultrastructural Pathology 05/2013; 37(3):183-90. DOI:10.3109/01913123.2012.756092 · 1.13 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Giant cell tumor (GCT) of the bone is a benign but locally aggressive bone neoplasm with a strong tendency to develop local recurrent and metastatic disease. Thus, it provides a useful model system for the identification of biological mechanisms involved in bone tumor progression and metastasis. This study profiled 24 cases of recurrent versus primary bone GCT tissues using QuantiGene 2.0 Multiplex Arrays that included Human p53 80-Plex Panels and Human Stem Cell 80-Plex Panels. A total of 32 differentially expressed genes were identified, including the 20 most upregulated genes and the 12 most downregulated genes in recurrent GCT. The genes identified are related to cell growth, adhesion, apoptosis, signal transduction and bone formation. Furthermore, iSubpathwayMiner analyses were performed to identify significant biological pathway regions (subpathway) associated with this disease. The pathway analysis identified 11 statistically significant enriched subpathways, including pathways in cancer, p53 signaling pathway, osteoclast differentiation pathway and Wnt signaling pathway. Among these subpathways, four genes (IGF1, MDM2, STAT1 and RAC1) were presumed to play an important role in bone GCT recurrence. The differentially expressed MDM2 protein was immunohistochemically confirmed in the recurrent versus primary bone GCT tissues. This study identified differentially expressed genes and their subpathways in recurrent GCT, which may serve as potential biomarkers for the prediction of GCT recurrence.
    International Journal of Oncology 06/2014; 45(3). DOI:10.3892/ijo.2014.2501 · 2.77 Impact Factor


Available from
May 28, 2014