FOXO1 mediates RANKL-induced osteoclast formation and activity
#MMPMID25694609
Wang Y
; Dong G
; Jeon HH
; Elazizi M
; La LB
; Hameedaldeen A
; Xiao E
; Tian C
; Alsadun S
; Choi Y
; Graves DT
J Immunol
2015[Mar]; 194
(6
): 2878-87
PMID25694609
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We have previously shown that the transcription factor FOXO1 is elevated in
conditions with high levels of bone resorption. To investigate the role of FOXO1
in the formation of osteoclasts, we examined mice with lineage-specific deletion
of FOXO1 in osteoclast precursors and by knockdown of FOXO1 with small
interfering RNA. The receptor activator for NF-?B ligand (RANKL), a principal
bone-resorbing factor, induced FOXO1 expression and nuclear localization 2 d
after stimulation in bone marrow macrophages and RAW264.7 osteoclast precursors.
RANKL-induced osteoclast formation and osteoclast activity was reduced in half in
vivo and in vitro with lineage-specific FOXO1 deletion (LyzM.Cre(+)FOXO1(L/L))
compared with matched controls (LyzM.Cre(-)FOXO1(L/L)). Similar results were
obtained by knockdown of FOXO1 in RAW264.7 cells. Moreover, FOXO1-mediated
osteoclast formation was linked to regulation of NFATc1 nuclear localization and
expression as well as a number of downstream factors, including dendritic
cell-specific transmembrane protein, ATP6vod2, cathepsin K, and integrin ?v.
Lastly, FOXO1 deletion reduced M-CSF-induced RANK expression and migration of
osteoclast precursors. In the present study, we provide evidence that FOXO1 plays
a direct role in osteoclast formation by mediating the effect of RANKL on NFATc1
and several downstream effectors. This is likely to be significant because FOXO1
and RANKL are elevated in osteolytic conditions.
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