Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis
DNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days...
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doaj-0596d2e367974e3c8527912d43d882372021-02-18T00:01:49ZengMDPI AGBiomedicines2227-90592021-02-01919919910.3390/biomedicines9020199Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing OsteoclastogenesisUrara Tanaka0Shunichi Kajioka1Livia S. Finoti2Daniela B. Palioto3Denis F. Kinane4Manjunatha R. Benakanakere5Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pharmaceutical Sciences, School of Pharmacy at Fukuoka, International University of Health Welfare, Fukuoka 812-8582, JapanDepartment of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAPeriodontology Department, Bern Dental School, University of Bern, 3012 Bern, SwitzerlandDepartment of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days with Decitabine (5-aza-2′-deoxycytidine) (1 mg/kg/day) or vehicle treatment. We evaluated bone resorption, osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) and mRNA expression of anti-inflammatory molecules using cluster differentiation 14 positive (CD14<sup>+</sup>) monocytes from human peripheral blood. Our data showed that decitabine inhibited bone loss and osteoclast differentiation experimental periodontitis, and suppressed osteoclast CD14<sup>+</sup> human monocytes; and conversely, that it increased bone mineralization in osteoblastic cell line MC3T3-E1 in a concentration-dependent manner. In addition to increasing <i>IL10</i> (interleukin-10), <i>TGFB</i> (transforming growth factor beta-1) in CD14<sup>+</sup> monocytes, decitabine upregulated KLF2 (Krüppel-like factor-2) expression. Overexpression of KLF2 protein enhanced the transcription of <i>IL10</i> and <i>TGFB.</i> On the contrary, site-directed mutagenesis of <i>KLF2</i> binding site in <i>IL10</i> and <i>TFGB</i> abrogated luciferase activity in HEK293T cells. Decitabine reduces bone loss in a mouse model of periodontitis by inhibiting osteoclastogenesis through the upregulation of anti-inflammatory cytokines via KLF2 dependent mechanisms. DNA methyltransferase inhibitors merit further investigation as a possible novel therapy for periodontitis.https://www.mdpi.com/2227-9059/9/2/199periodontitisperiodontal bone-lossdecitabineKrüppel-like transcription factor-2interleukin-10transforming growth factor beta-1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Urara Tanaka Shunichi Kajioka Livia S. Finoti Daniela B. Palioto Denis F. Kinane Manjunatha R. Benakanakere |
spellingShingle |
Urara Tanaka Shunichi Kajioka Livia S. Finoti Daniela B. Palioto Denis F. Kinane Manjunatha R. Benakanakere Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis Biomedicines periodontitis periodontal bone-loss decitabine Krüppel-like transcription factor-2 interleukin-10 transforming growth factor beta-1 |
author_facet |
Urara Tanaka Shunichi Kajioka Livia S. Finoti Daniela B. Palioto Denis F. Kinane Manjunatha R. Benakanakere |
author_sort |
Urara Tanaka |
title |
Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis |
title_short |
Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis |
title_full |
Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis |
title_fullStr |
Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis |
title_full_unstemmed |
Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis |
title_sort |
decitabine inhibits bone resorption in periodontitis by upregulating anti-inflammatory cytokines and suppressing osteoclastogenesis |
publisher |
MDPI AG |
series |
Biomedicines |
issn |
2227-9059 |
publishDate |
2021-02-01 |
description |
DNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days with Decitabine (5-aza-2′-deoxycytidine) (1 mg/kg/day) or vehicle treatment. We evaluated bone resorption, osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) and mRNA expression of anti-inflammatory molecules using cluster differentiation 14 positive (CD14<sup>+</sup>) monocytes from human peripheral blood. Our data showed that decitabine inhibited bone loss and osteoclast differentiation experimental periodontitis, and suppressed osteoclast CD14<sup>+</sup> human monocytes; and conversely, that it increased bone mineralization in osteoblastic cell line MC3T3-E1 in a concentration-dependent manner. In addition to increasing <i>IL10</i> (interleukin-10), <i>TGFB</i> (transforming growth factor beta-1) in CD14<sup>+</sup> monocytes, decitabine upregulated KLF2 (Krüppel-like factor-2) expression. Overexpression of KLF2 protein enhanced the transcription of <i>IL10</i> and <i>TGFB.</i> On the contrary, site-directed mutagenesis of <i>KLF2</i> binding site in <i>IL10</i> and <i>TFGB</i> abrogated luciferase activity in HEK293T cells. Decitabine reduces bone loss in a mouse model of periodontitis by inhibiting osteoclastogenesis through the upregulation of anti-inflammatory cytokines via KLF2 dependent mechanisms. DNA methyltransferase inhibitors merit further investigation as a possible novel therapy for periodontitis. |
topic |
periodontitis periodontal bone-loss decitabine Krüppel-like transcription factor-2 interleukin-10 transforming growth factor beta-1 |
url |
https://www.mdpi.com/2227-9059/9/2/199 |
work_keys_str_mv |
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