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SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption
The mechanistic regulation of bone mass in aged animals is poorly understood. In this study, we examined the role of SIRT6, a longevity-associated factor, in osteocytes, using mice lacking Sirt6 in Dmp-1-expressing cells (cKO mice) and the MLO-Y4 osteocyte-like cell line. cKO mice exhibited increase...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10192395/ https://www.ncbi.nlm.nih.gov/pubmed/37198221 http://dx.doi.org/10.1038/s41598-023-33297-7 |
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author | Aobulikasimu, Alkebaier Liu, Tao Piao, Jinying Sato, Shingo Ochi, Hiroki Okawa, Atsushi Tsuji, Kunikazu Asou, Yoshinori |
author_facet | Aobulikasimu, Alkebaier Liu, Tao Piao, Jinying Sato, Shingo Ochi, Hiroki Okawa, Atsushi Tsuji, Kunikazu Asou, Yoshinori |
author_sort | Aobulikasimu, Alkebaier |
collection | PubMed |
description | The mechanistic regulation of bone mass in aged animals is poorly understood. In this study, we examined the role of SIRT6, a longevity-associated factor, in osteocytes, using mice lacking Sirt6 in Dmp-1-expressing cells (cKO mice) and the MLO-Y4 osteocyte-like cell line. cKO mice exhibited increased osteocytic expression of Sost, Fgf23 and senescence inducing gene Pai-1 and the senescence markers p16 and Il-6, decreased serum phosphate levels, and low-turnover osteopenia. The cKO phenotype was reversed in mice that were a cross of PAI-1-null mice with cKO mice. Furthermore, senescence induction in MLO-Y4 cells increased the Fgf23 and Sost mRNA expression. Sirt6 knockout and senescence induction increased HIF-1α binding to the Fgf23 enhancer sequence. Bone mass and serum phosphate levels were higher in PAI-1-null aged mice than in wild-type mice. Therefore, SIRT6 agonists or PAI-1 inhibitors may be promising therapeutic options for aging-related bone metabolism disruptions. |
format | Online Article Text |
id | pubmed-10192395 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-101923952023-05-19 SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption Aobulikasimu, Alkebaier Liu, Tao Piao, Jinying Sato, Shingo Ochi, Hiroki Okawa, Atsushi Tsuji, Kunikazu Asou, Yoshinori Sci Rep Article The mechanistic regulation of bone mass in aged animals is poorly understood. In this study, we examined the role of SIRT6, a longevity-associated factor, in osteocytes, using mice lacking Sirt6 in Dmp-1-expressing cells (cKO mice) and the MLO-Y4 osteocyte-like cell line. cKO mice exhibited increased osteocytic expression of Sost, Fgf23 and senescence inducing gene Pai-1 and the senescence markers p16 and Il-6, decreased serum phosphate levels, and low-turnover osteopenia. The cKO phenotype was reversed in mice that were a cross of PAI-1-null mice with cKO mice. Furthermore, senescence induction in MLO-Y4 cells increased the Fgf23 and Sost mRNA expression. Sirt6 knockout and senescence induction increased HIF-1α binding to the Fgf23 enhancer sequence. Bone mass and serum phosphate levels were higher in PAI-1-null aged mice than in wild-type mice. Therefore, SIRT6 agonists or PAI-1 inhibitors may be promising therapeutic options for aging-related bone metabolism disruptions. Nature Publishing Group UK 2023-05-17 /pmc/articles/PMC10192395/ /pubmed/37198221 http://dx.doi.org/10.1038/s41598-023-33297-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Aobulikasimu, Alkebaier Liu, Tao Piao, Jinying Sato, Shingo Ochi, Hiroki Okawa, Atsushi Tsuji, Kunikazu Asou, Yoshinori SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption |
title | SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption |
title_full | SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption |
title_fullStr | SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption |
title_full_unstemmed | SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption |
title_short | SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption |
title_sort | sirt6-pai-1 axis is a promising therapeutic target in aging-related bone metabolic disruption |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10192395/ https://www.ncbi.nlm.nih.gov/pubmed/37198221 http://dx.doi.org/10.1038/s41598-023-33297-7 |
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