Journal
CELL REPORTS
Volume 8, Issue 4, Pages 1210-1224Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.07.032
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Funding
- Kidney Research UK [RP9/2013]
- Wellcome Trust [WT092523MA]
- European Community [HEALTH-F4- 2010-241504]
- Medical Research Council
- Boehringer Ingelheim
- MRC [MR/M004716/1, MC_U120097112, MC_U120061454] Funding Source: UKRI
- Kidney Research UK [RP9/2013] Funding Source: researchfish
- Medical Research Council [MC_U120097112, MR/M004716/1, MC_U120061454] Funding Source: researchfish
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Macrophages can fuse to form osteoclasts in bone or multinucleate giant cells (MGCs) as part of the immune response. We use a systems genetics approach in rat macrophages to unravel their genetic determinants of multinucleation and investigate their role in both bone homeostasis and inflammatory disease. We identify a trans-regulated gene network associated with macrophage multinucleation and Kcnn4 as being the most significantly trans-regulated gene in the network and induced at the onset of fusion. Kcnn4 is required for osteoclast and MGC formation in rodents and humans. Genetic deletion of Kcnn4 reduces macrophage multinucleation through modulation of Ca2+ signaling, increases bone mass, and improves clinical outcome in arthritis. Pharmacological blockade of Kcnn4 reduces experimental glomerulonephritis. Our data implicate Kcnn4 in macrophage multinucleation, identifying it as a potential therapeutic target for inhibition of bone resorption and chronic inflammation.
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