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The polyphenol resveratrol promotes skeletal growth in mice through a sirtuin 1‐bone morphogenic protein 2 longevity axis
BACKGROUND AND PURPOSE: The polyphenol resveratrol (RSV) exists in high quantities in certain foods (e.g. grapes and nuts). However, the capacity of RSV to confer physiological health benefits and a biological mechanism through which this might occur remains unclear. EXPERIMENTAL APPROACH: Aged, RSV...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177622/ https://www.ncbi.nlm.nih.gov/pubmed/30125963 http://dx.doi.org/10.1111/bph.14477 |
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author | Zhao, Ming Ko, Seon‐Yle Garrett, I Ross Mundy, Gregory R Gutierrez, Gloria E Edwards, James R |
author_facet | Zhao, Ming Ko, Seon‐Yle Garrett, I Ross Mundy, Gregory R Gutierrez, Gloria E Edwards, James R |
author_sort | Zhao, Ming |
collection | PubMed |
description | BACKGROUND AND PURPOSE: The polyphenol resveratrol (RSV) exists in high quantities in certain foods (e.g. grapes and nuts). However, the capacity of RSV to confer physiological health benefits and a biological mechanism through which this might occur remains unclear. EXPERIMENTAL APPROACH: Aged, RSV‐treated (300 mg·kg(−1)·day(−1)) and genetically modified [endothelial NOS (eNOS(−/−))] female mice were assessed using histomorphometric and μCT analysis. Alongside in vivo analysis, molecular siRNA knockdown and pharmacological manipulation of eNOS, BMP2 and sirtuin 1 (SIRT1) and functional cellular assays in an osteoblast cell line panel, explored the mechanism through which RSV might impact overall bone volume. KEY RESULTS: RSV promoted osteoblast activity and bone growth in vivo. RSV dose‐dependently and simultaneously increased alkaline phosphatase (ALP) and eNOS levels. Similarly, NO‐donor treatment increased ALP, runt homology transcription factor 2, BMP2 and stimulated bone formation, whilst eNOS‐deficient mice displayed a bone loss phenotype. Moreover, RSV‐induced increase in ALP and BMP2 expression was blocked in eNOS(−/−) osteoblasts and by BMP‐inhibitor noggin. The longevity‐linked SIRT1 enzyme was positively regulated by RSV and SIRT1 deletion reduced eNOS, BMP2 and ALP. Like eNOS deletion, loss of SIRT1 blocked RSV‐induced osteoblast activity; however, SIRT1 levels remained unchanged in eNOS(−/−) mice, indicating RSV activation of SIRT1 stimulates BMP2 release via eNOS. This signalling axis is supported by decreased SIRT1, eNOS and BMP2 confirmed in old versus young bone. CONCLUSIONS AND IMPLICATIONS: These findings suggest a new mechanism of action in bone remodelling and the ageing skeleton, where RSV positively impacts bone homeostasis via SIRT1 activation of BMP2. |
format | Online Article Text |
id | pubmed-6177622 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61776222018-10-18 The polyphenol resveratrol promotes skeletal growth in mice through a sirtuin 1‐bone morphogenic protein 2 longevity axis Zhao, Ming Ko, Seon‐Yle Garrett, I Ross Mundy, Gregory R Gutierrez, Gloria E Edwards, James R Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: The polyphenol resveratrol (RSV) exists in high quantities in certain foods (e.g. grapes and nuts). However, the capacity of RSV to confer physiological health benefits and a biological mechanism through which this might occur remains unclear. EXPERIMENTAL APPROACH: Aged, RSV‐treated (300 mg·kg(−1)·day(−1)) and genetically modified [endothelial NOS (eNOS(−/−))] female mice were assessed using histomorphometric and μCT analysis. Alongside in vivo analysis, molecular siRNA knockdown and pharmacological manipulation of eNOS, BMP2 and sirtuin 1 (SIRT1) and functional cellular assays in an osteoblast cell line panel, explored the mechanism through which RSV might impact overall bone volume. KEY RESULTS: RSV promoted osteoblast activity and bone growth in vivo. RSV dose‐dependently and simultaneously increased alkaline phosphatase (ALP) and eNOS levels. Similarly, NO‐donor treatment increased ALP, runt homology transcription factor 2, BMP2 and stimulated bone formation, whilst eNOS‐deficient mice displayed a bone loss phenotype. Moreover, RSV‐induced increase in ALP and BMP2 expression was blocked in eNOS(−/−) osteoblasts and by BMP‐inhibitor noggin. The longevity‐linked SIRT1 enzyme was positively regulated by RSV and SIRT1 deletion reduced eNOS, BMP2 and ALP. Like eNOS deletion, loss of SIRT1 blocked RSV‐induced osteoblast activity; however, SIRT1 levels remained unchanged in eNOS(−/−) mice, indicating RSV activation of SIRT1 stimulates BMP2 release via eNOS. This signalling axis is supported by decreased SIRT1, eNOS and BMP2 confirmed in old versus young bone. CONCLUSIONS AND IMPLICATIONS: These findings suggest a new mechanism of action in bone remodelling and the ageing skeleton, where RSV positively impacts bone homeostasis via SIRT1 activation of BMP2. John Wiley and Sons Inc. 2018-09-18 2018-11 /pmc/articles/PMC6177622/ /pubmed/30125963 http://dx.doi.org/10.1111/bph.14477 Text en © 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Papers Zhao, Ming Ko, Seon‐Yle Garrett, I Ross Mundy, Gregory R Gutierrez, Gloria E Edwards, James R The polyphenol resveratrol promotes skeletal growth in mice through a sirtuin 1‐bone morphogenic protein 2 longevity axis |
title | The polyphenol resveratrol promotes skeletal growth in mice through a sirtuin 1‐bone morphogenic protein 2 longevity axis |
title_full | The polyphenol resveratrol promotes skeletal growth in mice through a sirtuin 1‐bone morphogenic protein 2 longevity axis |
title_fullStr | The polyphenol resveratrol promotes skeletal growth in mice through a sirtuin 1‐bone morphogenic protein 2 longevity axis |
title_full_unstemmed | The polyphenol resveratrol promotes skeletal growth in mice through a sirtuin 1‐bone morphogenic protein 2 longevity axis |
title_short | The polyphenol resveratrol promotes skeletal growth in mice through a sirtuin 1‐bone morphogenic protein 2 longevity axis |
title_sort | polyphenol resveratrol promotes skeletal growth in mice through a sirtuin 1‐bone morphogenic protein 2 longevity axis |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177622/ https://www.ncbi.nlm.nih.gov/pubmed/30125963 http://dx.doi.org/10.1111/bph.14477 |
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