State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Department of Hematology and Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
Genomics Proteomics Bioinformatics. 2018 Jun;16(3):172-186. doi: 10.1016/j.gpb.2018.04.005. Epub 2018 Jun 13.
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.
作为一种双氧酶，Ten-Eleven Translocation 2（TET2）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，但它对成熟造血细胞的影响尚未得到很好的描述。在这里，我们表明 Tet2 在破骨细胞发生中起着重要作用。Tet2 的缺失会损害破骨细胞前体细胞（巨噬细胞）的分化及其在体外向骨吸收性破骨细胞的成熟。此外，Tet2 小鼠表现出轻度的骨质增生，体内破骨细胞数量减少。巨噬细胞中 Tet2 的缺失导致一组与破骨细胞分化相关的基因的表达发生改变，如 Cebpa、Mafb 和 Nfkbiz。Tet2 缺失还导致 5-羟甲基胞嘧啶（5hmC）水平的全基因组改变，并改变与破骨细胞分化相关的特定巨噬细胞基因子集的表达。此外，Tet2 与 Runx1 相互作用并负调控其转录活性。我们的研究表明，Tet2 通过与 Runx1 相互作用和维持基因组 5hmC，控制破骨细胞分化和功能的一种新的分子机制。靶向 Tet2 及其途径可能是预防和治疗破骨细胞活性失调引起的异常骨量的潜在治疗策略。
