title: A novel inhibitor of vacuolar ATPase, FR202126, prevents alveolar bone destruction in experimental periodontitis in rats.
abstract: An acidic microenvironment formed by vacuolar ATPase (V-ATPase) expressed in plasma membranes of osteoclasts is thought to be indispensable for bone resorption. This study examined the efficacy of a novel V-ATPase inhibitor, FR202126, in reducing alveolar bone loss caused by experimental periodontitis in rats. FR202126 inhibited H+ transport in plasma membrane vesicles of murine osteoclasts, whereas FR202126 exerted no effect on H+ transport of mitochondrial ATPase or gastric H+,K+-ATPase, indicating that FR202126 is a specific inhibitor of V-ATPase. As expected from the mechanism, FR202126 remarkably inhibited in vitro bone resorption whatever bone resorptive factors were added. Moreover, FR202126 was also able to exert an inhibitory effect on in vivo bone resorption. Experimental periodontitis was induced by ligature wire tied around the contact between the first and second maxillary molars. Insertion of ligature wire for 7 days induced alveolar bone destruction by activating osteoclasts. Oral administration of FR202126 (u.i.d.) significantly prevented alveolar bone loss in experimental periodontitis which may offer a new approach to treatment of periodontal disease.
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., Tokyo, Japan. kazuaki.niikura@jp.astellas.com
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Niikura
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Takeshita
authors.forename: Noboru
authors.initials: N
authors.lastname: Chida
mesh_terms: D016301:Alveolar Bone Loss / Q000473:pathology / Q000517:prevention & control*; D000634:Aminoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D001862:Bone Resorption / Q000517:prevention & control; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D008026:Ligation; D008297:Male; D008439:Maxillary Diseases / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008963:Molar; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology; D010518:Periodontitis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D013997:Time Factors; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C508362:2,6-dichloro-N-(3-methyl-4-(3-methyl-2-oxo-1-imidazolidinyl)-8-quinolinyl)benzamide; D000634:Aminoquinolines; D001549:Benzamides; D025262:Vacuolar Proton-Translocating ATPases