title: Receptor-Activator of Nuclear KappaB Ligand Expression as a New Therapeutic Target in Primary Bone Tumors.
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.
authors.affiliation: Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yamagishi
authors.affiliation: Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawashima
authors.affiliation: Department of Orthopedic Surgery, Uonuma Kikan Hospital, Minamiuonuma, Niigata, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ogose
authors.affiliation: Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ariizumi
authors.affiliation: Department of Orthopedic Surgery, Niigata Cancer Center Hospital, Niigata, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Orthopedic Surgery, Niigata Cancer Center Hospital, Niigata, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hatano
authors.affiliation: Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Hotta
authors.affiliation: Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Endo
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017824:Bone Cysts, Aneurysmal / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000517:prevention & control; D002812:Chondroma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002813:Chondrosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000069448:Denosumab / Q000627:therapeutic use*; D005260:Female; D005357:Fibrous Dysplasia of Bone / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D018212:Giant Cell Tumor of Bone / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053245:RANK Ligand; D012333:RNA, Messenger; C505688:TNFSF11 protein, human; D000069448:Denosumab