Giant cell tumors of bone (GCTB) are locally aggressive osteolytic bone
tumors. Recently, some clinical trials have shown that
denosumab is a novel and effective therapeutic option for aggressive and recurrent GCTB. This study was performed to investigate the molecular mechanism underlying the
therapeutic effect of
denosumab. Comparative proteomic analyses were performed using GCTB samples which were taken before and after
denosumab treatment. Each expression profile was analyzed using the software program to further understand the affected biological network. One of identified
proteins was further evaluated by
gelatin zymography and an immunohistochemical analysis. We identified 13 consistently upregulated
proteins and 19 consistently downregulated
proteins in the pre- and post-
denosumab samples. Using these profiles, the software program identified molecular interactions between the differentially expressed
proteins that were indirectly involved in the RANK/RANKL pathway and in several non-canonical subpathways including the
Matrix metalloproteinase pathway. The data analysis also suggested that the identified
proteins play a critical functional role in the osteolytic process of GCTB. Among the most downregulated
proteins, the activity of MMP-9 was significantly decreased in the
denosumab-treated samples, although the residual stromal cells were found to express MMP-9 by an immunohistochemical analysis. The expression level of MMP-9 in the primary GCTB samples was not correlated with any clinicopathological factors, including patient outcomes. Although the replacement of
tumors by fibro-osseous tissue or the diminishment of osteoclast-like giant cells have been shown as
therapeutic effects of
denosumab, the
residual tumor after
denosumab treatment, which is composed of only stromal cells, might be capable of causing bone destruction; thus the therapeutic application of
denosumab would be still necessary for these lesions. We believe that the
protein expression patterns and the results of the network analysis will provide a better understanding of the effects of
denosumab administration in patients with GCTB.