Notch signaling induces root resorption via RANKL and IL-6 from hPDL cells.
In this study, we first investigated the expressions of Jagged1, Notch2, the receptor activator of nuclear factor-kappa B ligand (RANKL), and interleukin (IL)-6 in areas of root resorption during experimental tooth movement in rats in vivo. We then assessed the effects of compression force (CF) with or without GSI (an inhibitor of Notch signaling) on Jagged1, RANKL, and IL-6 release from human periodontal ligament (hPDL) cells. Twelve male 6-wk-old Wistar rats were subjected to an orthodontic force of 50 g to induce mesially tipping movement of the upper first molars for 7 d. The expression levels of tartrate-resistant acid phosphatase, Jagged1, Notch2, IL-6, and RANKL proteins in the dental root were determined using an immunohistochemical analysis. Furthermore, the effects of the CF on Jagged1, IL-6, and RANKL production were investigated using hPDL cells in vitro. The effects of the cell-conditioned medium obtained from the hPDL cells subjected to CF (CFM) and Jagged 1 on osteoclastogenesis of human osteoclast precursor cells (hOCPs) were also investigated. Under the conditions of experimental tooth movement in vivo, resorption lacunae with multinucleated cells were observed in the 50 g group. In addition, immunoreactivity for Jagged1, Notch2, IL-6, and RANKL was detected on day 7 in the PDL tissue subjected to the orthodontic force. In the in vitro study, the compression force increased the production of Jagged1, IL-6, and RANKL from the hPDL cells, whereas treatment with GSI inhibited the production of these factors in vitro. The osteoclastogenesis increased with the CFM and rhJagged1, and the increase in the osteoclastogenesis was almost inhibited by GSI. These results suggest that the Notch signaling response to excessive orthodontic forces stimulates the process of root resorption via RANKL and IL-6 production from hPDL cells.
Department of Orthodontics, Nihon University School of Dentistry at Matsudo, Matsudo, Japan.
J
J
Kikuta
Department of Orthodontics, Nihon University School of Dentistry at Matsudo, Matsudo, Japan yamaguchi.masaru@nihon-u.ac.jp.
M
M
Yamaguchi
Department of Orthodontics, Nihon University School of Dentistry at Matsudo, Matsudo, Japan.
M
M
Shimizu
Department of Orthodontics, Nihon University School of Dentistry at Matsudo, Matsudo, Japan.
T
T
Yoshino
Department of Orthodontics, Nihon University School of Dentistry at Matsudo, Matsudo, Japan.
K
K
Kasai
D000135:Acid Phosphatase / Q000032:analysis; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002135:Calcium-Binding Proteins / Q000032:analysis*; D018929:Cell Culture Techniques; D017077:Culture Media, Conditioned; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis*; D015850:Interleukin-6 / Q000032:analysis*; D007527:Isoenzymes / Q000032:analysis; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000032:analysis*; D009842:Oligopeptides / Q000494:pharmacology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010513:Periodontal Ligament / Q000737:chemistry* / Q000473:pathology; D053245:RANK Ligand / Q000032:analysis*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D051883:Receptor, Notch2 / Q000032:analysis* / Q000037:antagonists & inhibitors; D012391:Root Resorption / Q000209:etiology* / Q000473:pathology; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071681:Tartrate-Resistant Acid Phosphatase; D014087:Tooth Movement Techniques / Q000009:adverse effects; D014092:Tooth Root / Q000737:chemistry
D015415:Biomarkers; D002135:Calcium-Binding Proteins; D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D007527:Isoenzymes; C000606273:JAG1 protein, human; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D009842:Oligopeptides; D053245:RANK Ligand; D051883:Receptor, Notch2; D000072099:Serrate-Jagged Proteins; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D053829:Amyloid Precursor Protein Secretases
Notch signal; inflammatory cytokines; odontoclasts; orthodontic force; osteoclastogenesis; tooth movement