Abstract
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.
