Lyess Allas (doctorant), récompensé lors de la Journée normande de la recherche biomédicale 2017
le 14 novembre 2017
Lyess Allas (doctorant), récompensé lors de la Journée normande de la recherche biomédicale 2017
Il présentait les avancées de l'unité sur le programme EpiCarT qui vise à étudier le rôle de l'épigénétique, en particulier de la méthylation des histones, dans le cartilage, dont une partie a été publié très récemment dans Scientific Report (lire la publication)
Titre de la présentation :
EZH2 inhibition reduces IL-1β-mediated inflammation and increases anabolic gene expression in human chondrocytes
Auteurs :
Lyess ALLAS, Juliette AURY-LANDAS, Quitterie ROCHOUX, Céline BAZILLE, Marion BERTHELOT, Christophe CHESNEAU, Sylvain LECLERCQ, Karim BOUMEDIENE, Catherine BAUGE
Résumé de la communication :
Osteoarthritis (OA) is a rheumatic disease characterized by inflammation, cartilage hypertrophy and degradation. Recently, it has been reported that EZH2, a histone methyltransferase, is upregulated in OA cartilage and that its inhibition counteracts chondrocyte hypertrophy. In this study, we aimed to evaluate anti-inflammatory and proanabolic effect of EZH2 inhibitors in chondrocytes.
Inflammation was induced in vitro by incubating human primary chondrocytes with interleukin-1 β (IL-1β), a cytokine largely present in synovial liquid of OA patient and considered as one of the major mediator of cartilage degradation by upregulating matrix metalloproteases (MMP). EZH2 was inhibited by two pharmacological drugs, EPZ6438 (also called Tazemetostat) and DZNep. Inflammation was evaluated by PGE2 and NO release. Catabolism was investigated by MMP expression and release, and anabolism by Sox9 and type 2 collagen expression. Differentially expressed genes (DEG) regulated by DZNep were identified by whole-transcriptome microarray.
We showed that EZH2 inhibition reduces NO, PGE2 and MMP release induced by IL-1β. In addition, DNZep counteracted the effect of IL-1β on the expression of 81 protein-coding genes, including CITED2, an MMP inhibitor. Gene ontology enrichment analysis confirmed that DZNep counteracts IL-1β-induced expression of genes involved in cartilage matrix breakdown. Furthermore, we showed that besides their anti-inflammatory and anti-catabolic effects, DZNep and EPZ6438 act as chondroprotective molecules by up-regulating cartilage specific genes, such as COL2A1 and SOX9.
Overall, our results demonstrate that EZH2 inhibition counteracts inflammation and reduces expression of gene involved in cartilage matrix breakdown, and enhances chondrogenic gene expression. Thus, an epigenetic therapy targeting EZH2 may provide a promising strategy against osteoarthritis by reducing inflammation, cartilage breakdown, hypertrophy and favoring tissue repair.
Remerciements : Agence Nationale de la Recherche [ANR-15-CE14-0002-01], Région Normandie, Union Européenne [FEDER/FSE 2014-2020 – 16E00779/16P03685] et Société Française de Rhumatologie (SFR)
Dernière modification : 27 novembre 2018
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