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DOT1L safeguards cartilage homeostasis and protects against osteoarthritis

Osteoarthritis is the most prevalent and crippling joint disease, and lacks curative treatment, as the underlying molecular basis is unclear. Here, we show that DOT1L, an enzyme involved in histone methylation, is a master protector of cartilage health. Loss of DOT1L disrupts the molecular signature...

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Autores principales: Monteagudo, Silvia, Cornelis, Frederique M. F., Aznar-Lopez, Carolina, Yibmantasiri, Ploi, Guns, Laura-An, Carmeliet, Peter, Cailotto, Frédéric, Lories, Rik J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481839/
https://www.ncbi.nlm.nih.gov/pubmed/28627522
http://dx.doi.org/10.1038/ncomms15889
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author Monteagudo, Silvia
Cornelis, Frederique M. F.
Aznar-Lopez, Carolina
Yibmantasiri, Ploi
Guns, Laura-An
Carmeliet, Peter
Cailotto, Frédéric
Lories, Rik J.
author_facet Monteagudo, Silvia
Cornelis, Frederique M. F.
Aznar-Lopez, Carolina
Yibmantasiri, Ploi
Guns, Laura-An
Carmeliet, Peter
Cailotto, Frédéric
Lories, Rik J.
author_sort Monteagudo, Silvia
collection PubMed
description Osteoarthritis is the most prevalent and crippling joint disease, and lacks curative treatment, as the underlying molecular basis is unclear. Here, we show that DOT1L, an enzyme involved in histone methylation, is a master protector of cartilage health. Loss of DOT1L disrupts the molecular signature of healthy chondrocytes in vitro and causes osteoarthritis in mice. Mechanistically, the protective function of DOT1L is attributable to inhibition of Wnt signalling, a pathway that when hyper-activated can lead to joint disease. Unexpectedly, DOT1L suppresses Wnt signalling by inhibiting the activity of sirtuin-1 (SIRT1), an important regulator of gene transcription. Inhibition of SIRT1 protects against osteoarthritis triggered by loss of DOT1L activity. Modulating the DOT1L network might therefore be a therapeutic approach to protect the cartilage against osteoarthritis.
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spelling pubmed-54818392017-07-06 DOT1L safeguards cartilage homeostasis and protects against osteoarthritis Monteagudo, Silvia Cornelis, Frederique M. F. Aznar-Lopez, Carolina Yibmantasiri, Ploi Guns, Laura-An Carmeliet, Peter Cailotto, Frédéric Lories, Rik J. Nat Commun Article Osteoarthritis is the most prevalent and crippling joint disease, and lacks curative treatment, as the underlying molecular basis is unclear. Here, we show that DOT1L, an enzyme involved in histone methylation, is a master protector of cartilage health. Loss of DOT1L disrupts the molecular signature of healthy chondrocytes in vitro and causes osteoarthritis in mice. Mechanistically, the protective function of DOT1L is attributable to inhibition of Wnt signalling, a pathway that when hyper-activated can lead to joint disease. Unexpectedly, DOT1L suppresses Wnt signalling by inhibiting the activity of sirtuin-1 (SIRT1), an important regulator of gene transcription. Inhibition of SIRT1 protects against osteoarthritis triggered by loss of DOT1L activity. Modulating the DOT1L network might therefore be a therapeutic approach to protect the cartilage against osteoarthritis. Nature Publishing Group 2017-06-19 /pmc/articles/PMC5481839/ /pubmed/28627522 http://dx.doi.org/10.1038/ncomms15889 Text en Copyright © 2017, The Author(s) http://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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Monteagudo, Silvia
Cornelis, Frederique M. F.
Aznar-Lopez, Carolina
Yibmantasiri, Ploi
Guns, Laura-An
Carmeliet, Peter
Cailotto, Frédéric
Lories, Rik J.
DOT1L safeguards cartilage homeostasis and protects against osteoarthritis
title DOT1L safeguards cartilage homeostasis and protects against osteoarthritis
title_full DOT1L safeguards cartilage homeostasis and protects against osteoarthritis
title_fullStr DOT1L safeguards cartilage homeostasis and protects against osteoarthritis
title_full_unstemmed DOT1L safeguards cartilage homeostasis and protects against osteoarthritis
title_short DOT1L safeguards cartilage homeostasis and protects against osteoarthritis
title_sort dot1l safeguards cartilage homeostasis and protects against osteoarthritis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481839/
https://www.ncbi.nlm.nih.gov/pubmed/28627522
http://dx.doi.org/10.1038/ncomms15889
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