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EZH2 inhibition reduces cartilage loss and functional impairment related to osteoarthritis

Abstract : Histone methyltransferase EZH2 is upregulated during osteoarthritis (OA), which is the most widespread rheumatic disease worldwide, and a leading cause of disability. This study aimed to assess the impact of EZH2 inhibition on cartilage degradation, inflammation and functional disability. In vitro, gain and loss of EZH2 function were performed in human articular OA chondrocytes stimulated with IL-1β. In vivo, the effects of EZH2 inhibition were investigated on medial meniscectomy (MMX) OA mouse model. The tissue alterations were assayed by histology and the functional disabilities of the mice by actimetry and running wheel. In vitro, EZH2 overexpression exacerbated the action of IL-1β in chondrocytes increasing the expression of genes involved in inflammation, pain (NO, PGE2, IL6, NGF) and catabolism (MMPs), whereas EZH2 inhibition by a pharmacological inhibitor, EPZ-6438, reduced IL-1β effects. Ex vivo, EZH2 inhibition decreased IL-1β-induced degradation of cartilage. In vivo, intra-articular injections of the EZH2 inhibitor reduced cartilage degradation and improved motor functions of OA mice. This study demonstrates that the pharmacological inhibition of the histone methyl-transferase EZH2 slows the progression of osteoarthritis and improves motor functions in an experimental OA model, suggesting that EZH2 could be an effective target for the treatment of OA by reducing catabolism, inflammation and pain. Abbreviations DNZep 3-Deazanoplanocin A EZH2 Enhancer of Zest Homolog 2 GFP Green Fluorescent Protein H3K27 Lysine 27 of the histone 3 IL-1β Interleukin-1β IL-6 Interleukin 6 JMJD3 Jumonji Domain Containing 3 MMP Matrix metalloproteinase MMX Medial meniscectomy NGF Nerve Growth Factor NO Nitric oxide OA Osteoarthritis PGE2 Prostaglandin E2 Osteoarthritis (OA) is the most widespread rheumatic disease worldwide, and one of the main causes of pain and disability, reducing patient's quality of life 1. OA affects 1 in 3 people over age 65 and women more than men 2. In the United States, 22.7% of the adult population (52.5 million of persons) report having been diagnosed with OA by their physician. The impact on healthcare expenses is massive. The cost of knee OA alone is, for instance,
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https://hal-normandie-univ.archives-ouvertes.fr/hal-03003543
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Submitted on : Friday, November 13, 2020 - 11:53:29 AM
Last modification on : Tuesday, October 19, 2021 - 11:35:05 PM
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Lyess Allas, Sybille Brochard, Quitterie Rochoux, Jules Ribet, Cleo Dujarrier, et al.. EZH2 inhibition reduces cartilage loss and functional impairment related to osteoarthritis. Scientific Reports, Nature Publishing Group, 2020, 10 (1), ⟨10.1038/s41598-020-76724-9⟩. ⟨hal-03003543⟩

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