Nrf2 Activation Attenuates Both Orthodontic Tooth Movement and Relapse

• Published in: Journal of dental research Vol. 94; no. 6; pp. 787 - 794
• Main Authors: Kanzaki, H., Shinohara, F., Itohiya-Kasuya, K., Ishikawa, M., Nakamura, Y.
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01-06-2015; SAGE PUBLICATIONS, INC
• Subjects: Alveolar bone; Animals; Antioxidants - pharmacology; Catechin; Catechin - analogs & derivatives; Catechin - pharmacology; Cell adhesion & migration; Cell Line; Cytotoxicity; Dentistry; Enzymes; Epigallocatechin gallate; Flow cytometry; Free Radical Scavengers - pharmacology; Gene expression; Gene regulation; Gene transfer; Heme Oxygenase-1 - analysis; Intracellular; Intracellular signalling; Isothiocyanates - pharmacology; Lipid peroxidation; Macrophages; Macrophages - drug effects; Male; Medical research; Membrane Proteins - analysis; Mice; Mice, Inbred C57BL; Molars; NF-E2-Related Factor 2 - drug effects; NF-E2-Related Factor 2 - physiology; NRF2 protein; Nuclear transport; Orthodontics; Osteoclastogenesis; Osteoclasts; Osteoclasts - drug effects; Osteoclasts - physiology; Osteoprogenitor cells; Oxidative stress; Oxidative Stress - drug effects; Periodontium; Polymerase chain reaction; Proteins; RANK Ligand; Reactive oxygen species; Reactive Oxygen Species - analysis; Reactive Oxygen Species - antagonists & inhibitors; Recurrence; Root resorption; Signal Transduction - drug effects; Stem Cells - drug effects; Sulforaphane; Teeth; Tooth Movement Techniques - methods; TRANCE protein; Transcription; Canada; United States > US; Japan; heme oxygenase-1 (HO-1); Kelch-like ECH-associated protein 1 (Keap1); reactive oxygen species (ROS); osteoclast; oxidative stress; bone resorption
• ISSN: 0022-0345; 1544-0591
• DOI: 10.1177/0022034515577814

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.