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Giant cell tumor of bone (GCT) is a locally aggressive osteolytic tumor with metastasic potential. Its name is derived from the osteoclast-like multinucleated giant cells that are present in the tumor. In addition, two other cell types are present within GCT: mononucleated spindle-like stromal cells of osteoblastic origin, and round, CD68-positive monocytes. The stromal cells are considered the neoplastic component of GCT and are thought to promote the formation of the multinucleated giant cells. The latter have classically been implicated in bone destruction due to their morphological resemblance to osteoclasts. Evidence suggests that proteases, including members from the family of matrix metalloproteinases (MMPs), are involved in the collagen-degrading activity of the tumor. Type I collagen constitutes approximately 90% of the bone microenvironment, and the type I collagenases, MMP-1, MMP-8 and MMP-13 are capable of degrading the intact triple-helix of type I collagen, whereas other members of the MMP family are not. Here we report that the stromal cells of GCT produce type I collagenases and are capable of degrading type I collagen independent of the giant cells. GCT samples from primary tissue were collected with patient consent and stromal cells were isolated and grown in culture through a process of selective trypsinization. PCR, western blot analysis, and the use of a multiplex protein assay system revealed the presence of type I collagenases. Immunohistochemistry on paraffin-embedded tissue samples confirmed the presence of these collagenases in the stromal cells in vivo. The activity of these collagenases was determined by standardized collagenase degradation assays using stromal cell conditioned media. These results suggest that, contrary to popular belief, the stromal cells of GCT play a key role in bone destruction and that these cells act through an MMP-mediated mechanism that can be targeted to improve the clinical management of these tumors.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA