title: Evidence for the role of matrix metalloproteinase-13 in bone resorption by giant cell tumor of bone.
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.
authors.affiliation: McMaster University, Hamilton, Ontario, Canada L8V 5C2. isabella.mak@jcc.hhsc.ca
authors.forename: Isabella W Y
authors.initials: IW
authors.lastname: Mak
authors.forename: Eric P
authors.initials: EP
authors.lastname: Seidlitz
authors.forename: Robert W
authors.initials: RW
authors.lastname: Cowan
authors.forename: Robert E
authors.initials: RE
authors.lastname: Turcotte
authors.forename: Snezana
authors.initials: S
authors.lastname: Popovic
authors.forename: William C H
authors.initials: WC
authors.lastname: Wu
authors.forename: Gurmit
authors.initials: G
authors.lastname: Singh
authors.forename: Michelle
authors.initials: M
authors.lastname: Ghert
mesh_terms: D014408:Biomarkers, Tumor; D001859:Bone Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D002450:Cell Communication; D045744:Cell Line, Tumor; D002469:Cell Separation; D018212:Giant Cell Tumor of Bone / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D015726:Giant Cells / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000201:enzymology / Q000473:pathology; D010014:Osteolysis / Q000201:enzymology* / Q000473:pathology; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13