title: The dynamin inhibitor dynasore inhibits bone resorption by rapidly disrupting actin rings of osteoclasts.
abstract: The cytoskeletal organization of osteoclasts is required for bone resorption. Binding of dynamin with guanosine triphosphate (GTP) was previously suggested to be required for the organization of the actin cytoskeleton. However, the role of the GTPase activity of dynamin in the organization of the actin cytoskeleton as well as in the bone-resorbing activity of osteoclasts remains unclear. This study investigated the effects of dynasore, an inhibitor of the GTPase activity of dynamin, on the bone-resorbing activity of and actin ring formation in mouse osteoclasts in vitro and in vivo. Dynasore inhibited the formation of resorption pits in osteoclast cultures by suppressing actin ring formation and rapidly disrupting actin rings in osteoclasts. A time-lapse image analysis showed that dynasore shrank actin rings in osteoclasts within 30 min. The intraperitoneal administration of dynasore inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced trabecular bone loss in mouse femurs. These in vitro and in vivo results suggest that the GTPase activity of dynamin is critical for the bone-resorbing activity of osteoclasts and that dynasore is a seed for the development of novel anti-resorbing agents.
authors.affiliation: Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri-shi, Nagano, 399-0781, Japan.
authors.forename: Gnanasagar J
authors.initials: GJ
authors.lastname: Thirukonda
authors.affiliation: Department of Biochemistry, Matsumoto Dental University, Nagano, 399-0781, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Uehara
authors.affiliation: Department of Periodontology, Matsumoto Dental University, Nagano, 399-0781, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri-shi, Nagano, 399-0781, Japan.
authors.forename: Teruhito
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Shinshu University, Nagano, 390-8621, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri-shi, Nagano, 399-0781, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Mizoguchi
authors.affiliation: Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri-shi, Nagano, 399-0781, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Oral Implantology, Matsumoto Dental University, Nagano, 399-0781, Japan.
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Yagami
authors.affiliation: Department of Biochemistry, Matsumoto Dental University, Nagano, 399-0781, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Udagawa
authors.affiliation: Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri-shi, Nagano, 399-0781, Japan. ykoba@po.mdu.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kobayashi
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D034281:Dynamins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006835:Hydrazones / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D053245:RANK Ligand / Q000378:metabolism*
chemical_list: D000199:Actins; D006835:Hydrazones; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D034281:Dynamins
keywords: Actin ring; Bone resorption; Dynamin; Dynasore; Osteoclast