- Participants will acquire the latest knowledge on the implication of novel cartilage disease processes and markers using genome, omics, and system biology analyses.
11.1.1 - The Mitochondria in OA
Mitochondria and mitochondrial variation have been recognized during the last years as important factors in the development of osteoarthritis (OA). Mitochondria are the energy powerhouse of the cell that also regulate different processes involved in the pathogenesis of OA. These include inflammation, apoptosis, calcium metabolism and the generation of reactive oxygen/nitrogen species (ROS/RNS).
Mitochondria contain their own genetic material, mitochondrial DNA (mtDNA), which evolved by the sequential accumulation of mtDNA variants permitting humans to adapt to different climates. ROS and reactive metabolic intermediates from mitochondrial metabolism are both regulated in part by mtDNA and are some of the signals transmitting information between mitochondria and the nucleus. These signals are able to alter nuclear gene expression and, when disrupted, affect a number of cellular processes and metabolic pathways leading to disease. In this session I will review the influence of mtDNA variation on OA-associated phenotypes, including those related to metabolism, inflammation and even aging, as well as nuclear epigenetic regulation,. This influence also enables the use of specific mtDNA haplogroups as complementary diagnostic and prognostic biomarkers of disease.
11.1.4 - Regulation and Role of H3K27 methylation in cartilage
Epigenetic mechanisms such as DNA methylation, or histone modifications, and noncoding RNAs have been indicated as important contributors to maintain tissue homeostasis upon environmental challenges. In particular, epigenetic changes occur during chondrogenesis and in osteoarthritis (OA). Our recent work aims to investigate the role of the methylation on the lysine 27 of the histone 3 (H3K27) in cartilage destruction and pain during OA, as well as in chondrogenesis. Then, we assessed the utility of pharmacological modulators of H3K27 methylation in cartilage tissue engineering and for OA treatment.
We and others showed that Enhancer of Zest Homolog 2 (EZH2), the major histone methyltransferase that catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3), is upregulated in OA cartilage, and plays a major role in OA progression in vitro and in vivo, by regulating chondrocytes hypertrophy and catabolism. Proteomics analysis revealed also that the proteins whose expression was deregulated by EZH2 inhibition, are mainly involved in autophagy, oxidation-reduction process/glutathione metabolism, glycolysis/carbohydrate metabolic process, and immune system. In addition, we showed that intra-articular injections of EZH2 inhibitors improve disease progression and reduce pain in OA mice.
In addition, the H3K27me3 demethylases, which are called Jumonji domain-containing protein D3 (JMJD3, also named lysine-specific demethylase 6B, KDM6B) and Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX, also named KDM6A), are involved in chondrogenesis. While only JMJD3 is upregulated during chondrogenesis and is required to proper chondrocyte differentiation, the overexpression of either histone demethylase permits to improve chondrogenesis in vitro. Thus, whereas they are differently regulated, JMJD3 and UTX (the both H3K27me3 demethylases) have redundant roles during chondrogenesis as showed by transcriptomics and Chip-Seq analysis, which showed important overlapping targets. More precisely, only the inhibition of JMJD3 (but not UTX) is able to counteract chondrogenesis (by reducing the expression of Sox5, Sox6, Agrecan and Collagen type II), whereas the ectopic expression of either JMJD3 or UTX led demethylation of H3K27 at loci of cartilage genes causing an increased expression of agrecan, collagen type II in in vitro model of chondrogenesis. In a context of cartilage engineering, the overexpression of either JMJD3 or UTX could favor cartilage formation and collagen expression.
Together, these results show the importance to investigate epigenetic markers in cartilage in order to identify new putative drugs against osteoarthritis or improve cartilage tissue engineering process.
Allas L, Brochard S, Rochoux Q, Ribet J, Dujarrier C, Veyssiere A, Aury-Landas J, Grard O, Leclercq S, Vivien D, Ea HK, Maubert E, Cohen-Solal M, Boumediene K, Agin V, Baugé C. EZH2 inhibition reduces cartilage loss and functional impairment related to osteoarthritis. Sci Rep. 2020 Nov 11;10(1):19577. doi: 10.1038/s41598-020-76724-9. PMID: 33177650; PMCID: PMC7658239.
Allas L, Rochoux Q, Leclercq S, Boumédiene K, Baugé C. Development of a simple osteoarthritis model useful to predict in vitro the anti-hypertrophic action of drugs. Lab Invest. 2020 Jan;100(1):64-71. doi: 10.1038/s41374-019-0303-0. Epub 2019 Aug 13. PMID: 31409892.
Allas L, Boumédiene K, Baugé C. Epigenetic dynamic during endochondral ossification and articular cartilage development. Bone. 2019 Mar;120:523-532. doi: 10.1016/j.bone.2018.10.004. Epub 2018 Oct 6. PMID: 30296494.
Aury-Landas J, Bazille C, Allas L, Bouhout S, Chesneau C, Leclercq S, Boumédiene K, Baugé C. Anti-inflammatory and chondroprotective effects of the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A, in human articular chondrocytes. Sci Rep. 2017 Jul 25;7(1):6483. doi: 10.1038/s41598-017-06913-6. PMID: 28744016; PMCID: PMC5526903.
This work was supported by the Agence Nationale de la Recherche [ANR-15-CE14-0002-01], Normandy County Council (EpiCart and Handiform projects) and the European Union in the framework of the ERDF-ESF operationnal programme 2014-2020 [FEDER/FSE 2014-2020 – 16E00779/16P03685], and Société Française de Rhumatologie (SFR).