title: Bis-enoxacin inhibits bone resorption and orthodontic tooth movement.
abstract: Enoxacin inhibits binding between the B-subunit of vacuolar H(+)-ATPase (V-ATPase) and microfilaments, and also between osteoclast formation and bone resorption in vitro. We hypothesized that a bisphosphonate derivative of enoxacin, bis-enoxacin (BE), which was previously studied as a bone-directed antibiotic, might have similar activities. BE shared a number of characteristics with enoxacin: It blocked binding between the recombinant B-subunit and microfilaments and inhibited osteoclastogenesis in cell culture with IC50s of about 10 µM in each case. BE did not alter the relative expression levels of various osteoclast-specific proteins. Even though tartrate-resistant acid phosphatase 5b was expressed, proteolytic activation of the latent pro-enzyme was inhibited. However, unlike enoxacin, BE stimulated caspase-3 activity. BE bound to bone slices and inhibited bone resorption by osteoclasts on BE-coated bone slices in cell culture. BE reduced the amount of orthodontic tooth movement achieved in rats after 28 days. Analysis of these data suggests that BE is a novel anti-resorptive molecule that is active both in vitro and in vivo and may have clinical uses.
  
  
  BACKGROUND
  BE, bis-enoxacin; V-ATPase, vacuolar H(+)-ATPase; TRAP, tartrate-resistant acid phosphatase; αMEM D10, minimal essential media, alpha modification with 10% fetal bovine serum; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; RANKL, receptor activator of nuclear factor kappa B-ligand; NFATc1, nuclear factor of activated T-cells; ADAM, a disintegrin and metalloprotease domain; OTM, orthodontic tooth movement.
authors: Department of Orthodontics, University of Florida College of Dentistry, Gainesville, FL 32610, USA.
authors: E J
authors: EJ
authors: Toro
authors: J
authors: J
authors: Zuo
authors: A
authors: A
authors: Gutierrez
authors: A
authors: A
authors: Guiterrez
authors: R L
authors: RL
authors: La Rosa
authors: A J
authors: AJ
authors: Gawron
authors: V
authors: V
authors: Bradaschia-Correa
authors: V
authors: V
authors: Arana-Chavez
authors: C
authors: C
authors: Dolce
authors: M F
authors: MF
authors: Rivera
authors: L
authors: L
authors: Kesavalu
authors: I
authors: I
authors: Bhattacharyya
authors: J K
authors: JK
authors: Neubert
authors: L S
authors: LS
authors: Holliday
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D016301:Alveolar Bone Loss / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology; D015365:Enoxacin / Q000494:pharmacology*; D008297:Male; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D010010:Osteoclasts / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014087:Tooth Movement Techniques; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors
chemical_list: D004164:Diphosphonates; D019384:Nucleic Acid Synthesis Inhibitors; D015365:Enoxacin; D053148:Caspase 3; D025262:Vacuolar Proton-Translocating ATPases
keywords: V-ATPase; alendronate; anti-resorptive; microfilaments; osteoclast; osteoclastogenesis
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