title: Inhibition of the RANK/RANKL signaling with osteoprotegerin prevents castration-induced acceleration of bone metastasis in castration-insensitive prostate cancer.
abstract: Androgen deprivation therapy (ADT) for patients with metastatic or locally advanced prostate cancer reduces bone mineral density by stimulating receptor activator of nuclear factor kappa-B (RANK) signaling in osteoclasts. The involvement of the RANK/RANKL signaling in ADT-induced acceleration of bone metastasis in castration-insensitive prostate cancer was examined in a murine model using osteoprotegerin (OPG). Male Balb/c nude mice were divided into three groups: the non-castration, castration, and castration + OPG groups. PC-3M-luc-C6 was injected into the left ventricle of the mice. Recombinant OPG was injected intravenously twice weekly in the castration + OPG group. In-vivo imaging system (IVIS®) determined that the prevalence and photon counts of bone metastasis in the castration group were significantly higher than that in the non-castration and castration + OPG groups. The mean number of RANKL-positive osteoblasts and the mean serum RANKL level in the castration group were significantly higher than those in the non-castration group. RANKL-enhanced activation of osteoclasts was attenuated in the castration + OPG group. These results suggest that the mechanisms of RANK/RANKL signaling are involved in the ADT-induced acceleration of bone metastasis in castration-insensitive prostate cancer.
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Takayama
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan; AMED-CREST, Japan Science and Technology Agency, Tokyo, Japan. Electronic address: takamitu@doc.med.akita-u.ac.jp.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan; AMED-CREST, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Narita
authors.affiliation: Iwate Prefectural Isawa Hospital, Iwate, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Maita
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan; AMED-CREST, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Mingguo
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Numakura
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuruta
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Maeno
authors.affiliation: Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Satoh
authors.affiliation: Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Tsuchiya
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan; AMED-CREST, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Habuchi
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015519:Bone Density / Q000187:drug effects; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009919:Orchiectomy; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D053244:Osteoprotegerin / Q000494:pharmacology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000097:blood / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000071681:Tartrate-Resistant Acid Phosphatase / Q000097:blood; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011994:Recombinant Proteins; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C506031:Tnfrsf11b protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: Bone metastasis; Castration; Osteoclast; Osteoprotegerin; Prostate cancer; Receptor activator of nuclear factor kappa-B ligand