摘要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.