title: Protein Expression Profiling of Giant Cell Tumors of Bone Treated with Denosumab.
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.
authors: Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors: Kenta
authors: K
authors: Mukaihara
authors: Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors: Yoshiyuki
authors: Y
authors: Suehara
authors: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors: Shinji
authors: S
authors: Kohsaka
authors: Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors: Keisuke
authors: K
authors: Akaike
authors: Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors: Yu
authors: Y
authors: Tanabe
authors: Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors: Daisuke
authors: D
authors: Kubota
authors: Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors: Midori
authors: M
authors: Ishii
authors: Laboratory of Biochemical Analysis, Central Laboratory of Medical Sciences, Juntendo University School of Medicine, Tokyo, Japan.
authors: Tsutomu
authors: T
authors: Fujimura
authors: Laboratory of Biochemical Analysis, Central Laboratory of Medical Sciences, Juntendo University School of Medicine, Tokyo, Japan.
authors: Saiko
authors: S
authors: Kazuno
authors: Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors: Taketo
authors: T
authors: Okubo
authors: Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors: Tatsuya
authors: T
authors: Takagi
authors: Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Takashi
authors: T
authors: Yao
authors: Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors: Kazuo
authors: K
authors: Kaneko
authors: Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Tsuyoshi
authors: T
authors: Saito
mesh_terms: D000328:Adult; D000483:Alleles; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy*; D001842:Bone and Bones / Q000187:drug effects*; D000069448:Denosumab / Q000627:therapeutic use*; D005260:Female; D005780:Gelatin / Q000737:chemistry; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D018212:Giant Cell Tumor of Bone / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D020543:Proteome; D040901:Proteomics; D012984:Software; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D050071:Bone Density Conservation Agents; D020543:Proteome; D000069448:Denosumab; D005780:Gelatin; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9