DOT1L safeguards cartilage homeostasis and protects against osteoarthritis.
DOT1L safeguards cartilage homeostasis and protects against osteoarthritis.
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DOI：
10.1038/ncomms15889
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发表时间：
2017-06-19
影响因子：
16.6
通讯作者：
Lories RJ
中科院分区：
文献类型：
--
作者：
Monteagudo S;Cornelis FMF;Aznar-Lopez C;Yibmantasiri P;Guns LA;Carmeliet P;Cailotto F;Lories RJ
骨关节炎是最普遍和致残的关节疾病，缺乏治愈性治疗，因为潜在的分子基础尚不清楚。在这里，我们表明DOT 1 L，一种参与组蛋白甲基化的酶，是软骨健康的主要保护者。DOT 1 L的缺失破坏了体外健康软骨细胞的分子特征，并导致小鼠骨关节炎。从机制上讲，DOT 1 L的保护功能可归因于Wnt信号传导的抑制，Wnt信号传导是一种当过度激活时可导致关节疾病的途径。出乎意料的是，DOT 1 L通过抑制sirtuin-1（SIRT 1）的活性来抑制Wnt信号传导，SIRT 1是基因转录的重要调节因子。SIRT 1的抑制可防止DOT 1 L活性丧失引发的骨关节炎。因此，调节DOT 1 L网络可能是保护软骨免受骨关节炎的治疗方法。DOT 1 L是通过人类GWAS与骨关节炎相关的少数基因之一。在这里，作者表明DOT 1 L依赖性组蛋白甲基化通过SIRT 1依赖性抑制经典WNT信号传导来保护关节软骨细胞的稳态，并且DOT 1 L的抑制可以驱动小鼠骨关节炎疾病。
Osteoarthritis is the most prevalent and crippling joint disease, and lacks curative treatment, as the underlying molecular basis is unclear. Here, we show that DOT1L, an enzyme involved in histone methylation, is a master protector of cartilage health. Loss of DOT1L disrupts the molecular signature of healthy chondrocytes in vitro and causes osteoarthritis in mice. Mechanistically, the protective function of DOT1L is attributable to inhibition of Wnt signalling, a pathway that when hyper-activated can lead to joint disease. Unexpectedly, DOT1L suppresses Wnt signalling by inhibiting the activity of sirtuin-1 (SIRT1), an important regulator of gene transcription. Inhibition of SIRT1 protects against osteoarthritis triggered by loss of DOT1L activity. Modulating the DOT1L network might therefore be a therapeutic approach to protect the cartilage against osteoarthritis. DOT1L is one of the few genes linked to osteoarthritis by human GWAS. Here the authors show that DOT1L-dependent histone methylation protects homeostasis of articular chondrocytes by SIRT1-dependent inhibition of canonical WNT signalling, and that inhibition of DOT1L can drive osteoarthritic disease in mice.