Abstract
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.
Highlights
Giant cell tumors of bone (GCTB) are rare benign, but locally aggressive lesions that are associated with significant bone destruction and soft tissue extension [1]
To identify the protein expression profiles that were associated with denosumab treatment, we performed a comparative proteomic analysis using samples that were obtained before denosumab treatment and after denosumab treatment
The therapeutic effect of denosumab against GCTB depends on the inhibition of osteoclast activity through the RANK/receptor activator of nuclear factor kappa-B ligand (RANKL) pathway [22]
Summary
Giant cell tumors of bone (GCTB) are rare benign, but locally aggressive lesions that are associated with significant bone destruction and soft tissue extension [1]. GCTB is composed of three main cellular components of mesenchymal fibroblast-like stromal cells which highly express the receptor activator of nuclear factor kappa-B ligand (RANKL); some of the rounded mononuclear cells and osteoclast-like multinucleated giant cells express RANK [4,5,6]. These cellular components interact with various factors and play a significant role in the osteolytic process, leading to bone destruction. Endogenous osteoprotegerin (OPG) inhibits both differentiation and function of osteoclasts by competing for and neutralizing RANKL [9]
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