Anti-inflammatory and chondroprotective effects of the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A, in human articular chondrocytes

Abstract 3-Deazaneplanocin A (DZNep) is an inhibitor of S-Adenosyl-L-Homocysteine Hydrolase (SAHH) known to inhibit EZH2, a histone methylase upregulated during osteoarthritis. In this study, we assessed its effects in human articular chondrocytes. Anti-inflammatory effects were assessed by Nitric O...

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Autores principales:	Juliette Aury-Landas, Céline Bazille, Lyess Allas, Sara Bouhout, Christophe Chesneau, Sylvain Leclercq, Karim Boumédiene, Catherine Baugé
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c493f3d217a94a09bb3338b657f3985e
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spelling	oai:doaj.org-article:c493f3d217a94a09bb3338b657f3985e2021-12-02T15:04:59ZAnti-inflammatory and chondroprotective effects of the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A, in human articular chondrocytes10.1038/s41598-017-06913-62045-2322https://doaj.org/article/c493f3d217a94a09bb3338b657f3985e2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06913-6https://doaj.org/toc/2045-2322Abstract 3-Deazaneplanocin A (DZNep) is an inhibitor of S-Adenosyl-L-Homocysteine Hydrolase (SAHH) known to inhibit EZH2, a histone methylase upregulated during osteoarthritis. In this study, we assessed its effects in human articular chondrocytes. Anti-inflammatory effects were assessed by Nitric Oxide (NO), Prostaglandin E2 (PGE2) and Metalloprotease (MMP) release in IL-1β-stimulated chondrocytes. MAPK and NFκB activation was analyzed by western blotting. Differentially expressed genes (DEG) regulated by DZNep were identified by whole-transcriptome microarray. DZNep inhibited SAHH activity and was not toxic. It counteracted NO, PGE2 and MMP release, and reduced MAPK activation induced by IL-1β. By whole-transcriptome analysis, we identified that DNZep counteracts the effect of IL-1β on the expression of 81 protein-coding genes, including CITED2, an MMP inhibitor. These genes are organized in a protein-protein network centred on EGR1, which is known to functionally interact with EZH2. Gene ontologies enrichment analysis confirmed that DZNep counteracts IL-1β-induced expression of genes involved in cartilage matrix breakdown (MMPs and ADAMTS). In addition, DZNep up-regulated cartilage specific genes, such as COL2A1 and SOX9, suggesting a chondroprotective effect of DZNep. DZNep exhibits anti-inflammatory effects, and regulates genes implicated in chondroprotective response in human articular chondrocytes, suggesting that inhibitors of S-adenosylmethionine-dependent methyltransferases could be effective treatments for OA.Juliette Aury-LandasCéline BazilleLyess AllasSara BouhoutChristophe ChesneauSylvain LeclercqKarim BoumédieneCatherine BaugéNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Juliette Aury-Landas Céline Bazille Lyess Allas Sara Bouhout Christophe Chesneau Sylvain Leclercq Karim Boumédiene Catherine Baugé Anti-inflammatory and chondroprotective effects of the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A, in human articular chondrocytes
description	Abstract 3-Deazaneplanocin A (DZNep) is an inhibitor of S-Adenosyl-L-Homocysteine Hydrolase (SAHH) known to inhibit EZH2, a histone methylase upregulated during osteoarthritis. In this study, we assessed its effects in human articular chondrocytes. Anti-inflammatory effects were assessed by Nitric Oxide (NO), Prostaglandin E2 (PGE2) and Metalloprotease (MMP) release in IL-1β-stimulated chondrocytes. MAPK and NFκB activation was analyzed by western blotting. Differentially expressed genes (DEG) regulated by DZNep were identified by whole-transcriptome microarray. DZNep inhibited SAHH activity and was not toxic. It counteracted NO, PGE2 and MMP release, and reduced MAPK activation induced by IL-1β. By whole-transcriptome analysis, we identified that DNZep counteracts the effect of IL-1β on the expression of 81 protein-coding genes, including CITED2, an MMP inhibitor. These genes are organized in a protein-protein network centred on EGR1, which is known to functionally interact with EZH2. Gene ontologies enrichment analysis confirmed that DZNep counteracts IL-1β-induced expression of genes involved in cartilage matrix breakdown (MMPs and ADAMTS). In addition, DZNep up-regulated cartilage specific genes, such as COL2A1 and SOX9, suggesting a chondroprotective effect of DZNep. DZNep exhibits anti-inflammatory effects, and regulates genes implicated in chondroprotective response in human articular chondrocytes, suggesting that inhibitors of S-adenosylmethionine-dependent methyltransferases could be effective treatments for OA.
format	article
author	Juliette Aury-Landas Céline Bazille Lyess Allas Sara Bouhout Christophe Chesneau Sylvain Leclercq Karim Boumédiene Catherine Baugé
author_facet	Juliette Aury-Landas Céline Bazille Lyess Allas Sara Bouhout Christophe Chesneau Sylvain Leclercq Karim Boumédiene Catherine Baugé
author_sort	Juliette Aury-Landas
title	Anti-inflammatory and chondroprotective effects of the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A, in human articular chondrocytes
title_short	Anti-inflammatory and chondroprotective effects of the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A, in human articular chondrocytes
title_full	Anti-inflammatory and chondroprotective effects of the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A, in human articular chondrocytes
title_fullStr	Anti-inflammatory and chondroprotective effects of the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A, in human articular chondrocytes
title_full_unstemmed	Anti-inflammatory and chondroprotective effects of the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A, in human articular chondrocytes
title_sort	anti-inflammatory and chondroprotective effects of the s-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin a, in human articular chondrocytes
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/c493f3d217a94a09bb3338b657f3985e
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Anti-inflammatory and chondroprotective effects of the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A, in human articular chondrocytes

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