Receptor-Activator of Nuclear KappaB Ligand Expression as a New Therapeutic Target in Primary Bone Tumors.

Tetsuro Yamagishi,Akira Ogose,Taro Sasaki,Hiroshi Hatano,Hiroyuki Kawashima,Takashi Ariizumi,Naoto Endo,Tetsuo Hotta,Sakamuri V Reddy

doi:10.1371/journal.pone.0154680

Tetsuro Yamagishi, Akira Ogose + Show 7 more

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https://doi.org/10.1371/journal.pone.0154680

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Journal: PloS one	Publication Date: May 10, 2016
Citations: 41	License type: CC BY 4.0

Affiliation: Niigata University, Niigata Cancer Center Hospital

Abstract

The receptor-activator of nuclear kappaB ligand (RANKL) signaling pathway plays an important role in the regulation of bone growth and mediates the formation and activation of osteoclasts. Osteoclasts are involved in significant bone resorption and destruction. Denosumab is a fully human monoclonal antibody against RANKL that specifically inhibits osteoclast differentiation and bone resorption. It has been approved for use for multiple myeloma and bone metastases, as well as for giant cell tumor of bone. However, there is no previous report quantitatively, comparing RANKL expression in histologically varied bone tumors. Therefore, we analyzed the mRNA level of various bone tumors and investigated the possibility of these tumors as a new therapeutic target for denosumab. We examined RANKL mRNA expression in 135 clinical specimens of primary and metastatic bone tumors using real-time PCR. The relative quantification of mRNA expression levels was performed via normalization with RPMI8226, a human multiple myeloma cell line that is recognized to express RANKL. Of 135 cases, 64 were also evaluated for RANKL expression by using immunohistochemistry. Among all of the tumors investigated, RANKL expression and the RANKL/osteoprotegerin ratio were highest in giant cell tumor of bone. High RANKL mRNA expression was observed in cases of aneurysmal bone cyst, fibrous dysplasia, osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic carcinoma. RANKL-positive stromal cells were detected in six cases: five cases of GCTB and one case of fibrous dysplasia. The current study findings indicate that some primary bone tumors present new therapeutic targets for denosumab, particularly those tumors expressing RANKL and those involving bone resorption by osteoclasts.

Highlights

The receptor-activator of nuclear kappa B ligand (RANKL) signaling pathway plays an important role in the regulation of bone growth and turnover
Denosumab is approved as a therapeutic agent for the treatment of multiple myeloma, bone metastases from solid cancer, and giant cell tumor of bone (GCTB), all of which express RANKL and involve osteoclast activation [4]
Mak et al reported that biopsy specimens before denosumab showed abundant osteoclast-like giant cells, and operative specimens following denosumab treatment showed severe elimination of osteoclast-like giant cells in GCTB [16]

Summary

Introduction

The receptor-activator of nuclear kappa B ligand (RANKL) signaling pathway plays an important role in the regulation of bone growth and turnover. RANKL is an essential regulator of osteoclastogenesis, and it is expressed on the surface of osteoblasts or stromal cells [1]. It mediates the formation and activation of multinucleated osteoclasts from RANK-positive mononuclear preosteoclasts and macrophages [1], and osteoclasts cause significant bone resorption and destruction in some pathological bone lesions. Denosumab is a fully human monoclonal antibody against RANKL that inhibits osteoclast differentiation and bone resorption by preventing the RANKL-mediated formation and activation of osteoclasts [4,5,6]. Denosumab is approved for the treatment of these tumors, which express RANKL and involve osteoclast activation [4]

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