title: Nrf2 activation attenuates both orthodontic tooth movement and relapse.
abstract: During orthodontic tooth movement, osteoclasts resorb the alveolar bone at the compress side of periodontium. Reactive oxygen species (ROS) works as intracellular signaling molecules of RANKL during osteoclastogenesis, although ROS has cytotoxicity against cells such as lipid oxidation. To deal with oxidative stress, cells have a defense system that is scavenging ROS by augmented antioxidative stress enzymes via transcriptional regulation with nuclear factor E2-related factor 2 (Nrf2). Previously, we reported that augmented antioxidative stress enzymes by Nrf2-gene transfer inhibited bone destruction. In the present study, we examined the effects of Nrf2 activation on osteoclastogenesis and, thereby, orthodontic tooth movement and orthodontic relapse. Mouse macrophage cell line RAW264.7 cells were used as osteoclast progenitor cells and stimulated with recombinant RANKL (100 ng/mL) with or without Nrf2 activator sulforaphane (SFN) and epigallocatechin gallate (EGCG) or ROS scavenger catechin. Osteoclastogenesis, resorption activity, and osteoclast marker gene expression were examined. Intracellular ROS was analyzed by flow cytometry. Maxillary first molars of C57BL6 male mice were moved palatally with 0.012-inch NiTi wire (100-mN force); SFN or EGCG was injected into the palatal gingiva once a week; and phosphate buffered saline was injected on the contralateral side. Tooth movement was monitored using a stone model with precise impression, and the amount of the tooth movement was compared among groups. SFN and EGCG significantly, but catechin weakly, inhibited RANKL-mediated osteoclastogenesis in vitro. Western blot analysis revealed that SFN and EGCG augmented the nuclear translocation of Nrf2 and the expression of anti-oxidative stress enzymes such as HO-1, although catechin did not. SFN and EGCG significantly, but catechin weakly, attenuated the intracellular ROS. Finally, animal experiment revealed that both SFN and EGCG successfully inhibited the orthodontic tooth movement. Additionally, SFN inhibited the relapse. These results suggest that Nrf2 activation could be therapeutic target for the anchorage enforcement in orthodontic treatment and pharmacologic retention against relapse.
authors: Tohoku University Hospital, Maxillo-oral Disorders, Sendai, Japan Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Japan kanzaki-h@tsurumi-u.ac.jp.
authors: H
authors: H
authors: Kanzaki
authors: Tohoku University Graduate School of Dentistry, Oral Microbiology, Sendai, Japan.
authors: F
authors: F
authors: Shinohara
authors: Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Japan.
authors: K
authors: K
authors: Itohiya-Kasuya
authors: Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Japan.
authors: M
authors: M
authors: Ishikawa
authors: Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Japan.
authors: Y
authors: Y
authors: Nakamura
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D016166:Free Radical Scavengers / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000032:analysis; D017879:Isothiocyanates / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000502:physiology*; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D053245:RANK Ligand; D017382:Reactive Oxygen Species / Q000032:analysis / Q000037:antagonists & inhibitors; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects; D013454:Sulfoxides; D014087:Tooth Movement Techniques / Q000379:methods*
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D017879:Isothiocyanates; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D053245:RANK Ligand; D017382:Reactive Oxygen Species; D013454:Sulfoxides; C505689:Tnfsf11 protein, mouse; D002392:Catechin; C045651:epigallocatechin gallate; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C016766:sulforaphane
keywords: Kelch-like ECH-associated protein 1 (Keap1); bone resorption; heme oxygenase-1 (HO-1); osteoclast; oxidative stress; reactive oxygen species (ROS)