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2017 ; 47
(1
): 66-79.e5
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Hypoxia-Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human
Macrophages and Suppresses Osteoclastogenesis
#MMPMID28723554
Murata K
; Fang C
; Terao C
; Giannopoulou EG
; Lee YJ
; Lee MJ
; Mun SH
; Bae S
; Qiao Y
; Yuan R
; Furu M
; Ito H
; Ohmura K
; Matsuda S
; Mimori T
; Matsuda F
; Park-Min KH
; Ivashkiv LB
Immunity
2017[Jul]; 47
(1
): 66-79.e5
PMID28723554
show ga
Hypoxia augments inflammatory responses and osteoclastogenesis by incompletely
understood mechanisms. We identified COMMD1 as a cell-intrinsic negative
regulator of osteoclastogenesis that is suppressed by hypoxia. In human
macrophages, COMMD1 restrained induction of NF-?B signaling and a transcription
factor E2F1-dependent metabolic pathway by the cytokine RANKL. Downregulation of
COMMD1 protein expression by hypoxia augmented RANKL-induced expression of
inflammatory and E2F1 target genes and downstream osteoclastogenesis. E2F1
targets included glycolysis and metabolic genes including CKB that enabled cells
to meet metabolic demands in challenging environments, as well as inflammatory
cytokine-driven target genes. Expression quantitative trait locus analysis linked
increased COMMD1 expression with decreased bone erosion in rheumatoid arthritis.
Myeloid deletion of Commd1 resulted in increased osteoclastogenesis in arthritis
and inflammatory osteolysis models. These results identify COMMD1 and an
E2F-metabolic pathway as key regulators of osteoclastogenic responses under
pathological inflammatory conditions and provide a mechanism by which hypoxia
augments inflammation and bone destruction.
|Adaptor Proteins, Signal Transducing/genetics/*metabolism
[MESH]