As a dioxygenase, Ten-Eleven Translocation 2 (TET2) catalyzes subsequent steps of 5-methylcytosine (5mC) oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hematopoietic stem cells, but its impact on mature hematopoietic cells is not well-characterized. Here we show that Tet2 plays an essential role in osteoclastogenesis. Deletion of Tet2 impairs the differentiation of osteoclast precursor cells (macrophages) and their maturation into bone-resorbing osteoclasts in vitro. Furthermore, Tet2?/? mice exhibit mild osteopetrosis, accompanied by decreased number of osteoclasts in vivo. Tet2 loss in macrophages results in the altered expression of a set of genes implicated in osteoclast differentiation, such as Cebpa, Mafb, and Nfkbiz. Tet2 deletion also leads to a genome-wide alteration in the level of 5-hydroxymethylcytosine (5hmC) and altered expression of a specific subset of macrophage genes associated with osteoclast differentiation. Furthermore, Tet2 interacts with Runx1 and negatively modulates its transcriptional activity. Our studies demonstrate a novel molecular mechanism controlling osteoclast differentiation and function by Tet2, that is, through interactions with Runx1 and the maintenance of genomic 5hmC. Targeting Tet2 and its pathway could be a potential therapeutic strategy for the prevention and treatment of abnormal bone mass caused by the deregulation of osteoclast activities.
Tet2作为双加氧酶，负责催化5-甲基胞嘧啶（5mC）氧化的后续步骤。Tet2在造血干细胞的自我更新、增殖和分化中发挥着关键作用，但其对成熟造血细胞的影响尚未得到很好的阐释。在这里，我们的工作表明Tet2在破骨细胞发生过程中起着至关重要的作用。Tet2的缺失破坏破骨细胞前体细胞（巨噬细胞）的体外分化及其成熟为具有骨吸收功能破骨细胞的能力。此外，Tet2-/-小鼠表现出轻度骨硬化，伴随着体内破骨细胞数量的减少。Tet2在巨噬细胞中的缺失导致一系列破骨细胞分化相关基因表达的紊乱，如Cebpa、Mafb和Nfkbiz。Tet2缺失同时引起巨噬细胞内与破骨细胞分化相关的特定基因集的5-羟甲基胞嘧啶（5hmC）水平和表达水平的改变。此外，Tet2与Runx1发生相互作用，并负调控其转录活性。我们的研究揭示了Tet2通过与Runx1相互作用以及维持基因组5hmC水平来调控破骨细胞分化和功能的新型分子机制。靶向TET2及其通路可能是防治由破骨细胞活性失调引起的骨密度异常的潜在治疗策略。





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