title: Comparative analysis of the effects of a novel vacuolar adenosine 5'-triphosphatase inhibitor, FR202126, and doxycycline on bone loss caused by experimental periodontitis in rats.
abstract: BACKGROUND
  Doxycycline is reported to inhibit alveolar bone destruction by blocking matrix metalloproteinases (MMPs). Nevertheless, MMPs are not involved in osteoclastic bone resorption; osteoclasts directly resorb bone. An acidic microenvironment, which is formed by vacuolar adenosine 5'-triphosphatase (V-ATPase) expressed in the plasma membranes of osteoclasts, is indispensable for osteoclastic bone resorption. In the present study, we investigated the potential role of the acidic environment on periodontal bone destruction using a novel and specific V-ATPase inhibitor, FR202126, which we compared to doxycycline.
  
  
  METHODS
  Inhibitory activity against in vitro bone resorption was examined by measuring the Ca2+ release from murine calvariae cultured for 6 days, which were treated with interleukin-1 (IL-1), IL-6, or parathyroid hormone. Experimental periodontitis was induced by a ligature wire tied around the contact between the first and second maxillary molars of male Wistar rats. FR202126 and doxycycline were administered orally once daily for 6 days. Seven days after tying, the maxillae were dissected and mesiodistal longitudinal paraffin sections, including interdental alveolar bone, were processed for histopathologic analysis.
  
  
  RESULTS
  FR202126 inhibited bone resorption almost completely in calvaria cultures induced by three stimulators, whereas doxycycline was unable to prevent in vitro bone resorption. Oral administration of FR202126 significantly prevented alveolar bone loss in experimental periodontitis. However, doxycycline did not inhibit alveolar bone destruction.
  
  
  CONCLUSIONS
  These results suggest that an acidic microenvironment plays a more important role than MMPs in periodontal alveolar bone destruction and that V-ATPase inhibitors may offer a new approach to the treatment of periodontal disease.
authors.affiliation: Data Management and Regulatory Support Department, Astellas Research Service, Ibaraki, Japan. kazuaki.niikura@jp.astellas.com
authors.forename: K
authors.initials: K
authors.lastname: Niikura
mesh_terms: D016301:Alveolar Bone Loss / Q000209:etiology / Q000517:prevention & control*; D000634:Aminoquinolines / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D004318:Doxycycline / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006863:Hydrogen-Ion Concentration; D008026:Ligation; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008815:Mice, Inbred Strains; D010010:Osteoclasts / Q000201:enzymology; D010518:Periodontitis / Q000150:complications; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*
chemical_list: C508362:2,6-dichloro-N-(3-methyl-4-(3-methyl-2-oxo-1-imidazolidinyl)-8-quinolinyl)benzamide; D000634:Aminoquinolines; D001549:Benzamides; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D025262:Vacuolar Proton-Translocating ATPases; D004318:Doxycycline