Shen Jie, Wang Cuicui, Li Daofeng, Xu Taotao, Myers Jason, Ashton John M, Wang Ting, Zuscik Michael J, McAlinden Audrey, O'Keefe Regis J
Department of Orthopaedic Surgery and.
Department of Genetics, Center for Genome Sciences and Systems Biology, School of Medicine, Washington University, St. Louis, Missouri, USA.
JCI Insight. 2017 Jun 15;2(12). doi: 10.1172/jci.insight.93612.
Osteoarthritis (OA) is the most common form of arthritis worldwide. It is a complex disease affecting the whole joint but is generally characterized by progressive degradation of articular cartilage. Recent genome-wide association screens have implicated distinct DNA methylation signatures in OA patients. We show that the de novo DNA methyltransferase (Dnmt) 3b, but not Dnmt3a, is present in healthy murine and human articular chondrocytes and its expression decreases in OA mouse models and in chondrocytes from human OA patients. Targeted deletion of Dnmt3b in murine articular chondrocytes results in an early-onset and progressive postnatal OA-like pathology. RNA-Seq and methylC-Seq analyses of Dnmt3b loss-of-function chondrocytes show that cellular metabolic processes are affected. Specifically, TCA metabolites and mitochondrial respiration are elevated. Importantly, a chondroprotective effect was found following Dnmt3b gain of function in murine articular chondrocytes in vitro and in vivo. This study shows that Dnmt3b plays a significant role in regulating postnatal articular cartilage homeostasis. Cellular pathways regulated by Dnmt3b in chondrocytes may provide novel targets for therapeutic approaches to treat OA.
骨关节炎（OA）是全球最常见的关节炎形式。它是一种影响整个关节的复杂疾病，其一般特征是关节软骨进行性退化。最近的全基因组关联筛查表明OA患者存在独特的DNA甲基化特征。我们发现，从头DNA甲基转移酶（Dnmt）3b而非Dnmt3a存在于健康的小鼠和人类关节软骨细胞中，并且其表达在OA小鼠模型以及人类OA患者的软骨细胞中降低。在小鼠关节软骨细胞中靶向缺失Dnmt3b会导致出生后早期出现并进行性发展的类似OA的病理变化。对Dnmt3b功能丧失的软骨细胞进行RNA测序和甲基化胞嘧啶测序分析表明，细胞代谢过程受到影响。具体而言，三羧酸循环（TCA）代谢物和线粒体呼吸增加。重要的是，在体外和体内小鼠关节软骨细胞中，Dnmt3b功能获得后发现了软骨保护作用。这项研究表明，Dnmt3b在调节出生后关节软骨稳态中起重要作用。Dnmt3b在软骨细胞中调节的细胞途径可能为治疗OA的治疗方法提供新的靶点。
