Abstract
ObjectivesIn osteoarthritis, methylation of lysine 79 on histone H3 (H3K79me), a protective epigenetic mechanism, is reduced. Histone methylation levels are dynamically regulated by histone methyltransferases and demethylases. Here, we aimed to identify which histone demethylases regulate H3K79me in cartilage and investigate whether their targeting protects against osteoarthritis.MethodsWe determined histone demethylase expression in human non-osteoarthritis and osteoarthritis cartilage using qPCR. The role of histone demethylase families and subfamilies on H3K79me was interrogated by treatment of human C28/I2 chondrocytes with pharmacological inhibitors, followed by western blot and immunofluorescence. We performed C28/I2 micromasses to evaluate effects on glycosaminoglycans by Alcian blue staining. Changes in H3K79me after destabilisation of the medial meniscus (DMM) in mice were determined by immunohistochemistry. Daminozide, a KDM2/7 subfamily inhibitor, was intra-articularly injected in mice upon DMM. Histone demethylases targeted by daminozide were individually silenced in chondrocytes to dissect their role on H3K79me and osteoarthritis.ResultsWe documented the expression signature of histone demethylases in human non-osteoarthritis and osteoarthritis articular cartilage. Inhibition of Jumonji-C demethylase family increased H3K79me in human chondrocytes. Blockade of KDM2/7 histone demethylases with daminozide increased H3K79me and glycosaminoglycans. In mouse articular cartilage, H3K79me decayed rapidly upon induction of joint injury. Early and sustained intra-articular treatment with daminozide enhanced H3K79me and exerted protective effects in mice upon DMM. Individual silencing of KDM7A/B demethylases in human chondrocytes demonstrated that KDM7A/B mediate protective effects of daminozide on H3K79me and osteoarthritis.ConclusionTargeting KDM7A/B histone demethylases could be an attractive strategy to protect joints against osteoarthritis.
Funder
FP7 Health
Dutch Arthritis Association
Fonds Wetenschappelijk Onderzoek
Leiden University Medical Center
Subject
General Biochemistry, Genetics and Molecular Biology,Immunology,Immunology and Allergy,Rheumatology
Reference36 articles.
1. Global Burden of Disease Collaborative Network . Global burden of disease study 2019 (GBD 2019) results. 2020. Available: http://ghdx.healthdata.org/gbdresults-tool
2. Osteoarthritis;Martel-Pelletier;Nat Rev Dis Primers,2016
3. Osteoarthritis year in review 2018: genetics and epigenetics;Jeffries;Osteoarthr Cartil,2019
4. The role of epigenetics in osteoarthritis: current perspective;Ramos;Curr Opin Rheumatol,2017
5. Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis
Cited by
16 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献