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Cell Rep. 2014 Aug 21;8(4):1210-24. doi: 10.1016/j.celrep.2014.07.032. Epub 2014 Aug 14.

Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory disease.

Author information

1
Departments of Orthopaedics and Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
2
Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, UK.
3
Integrative Genomics and Medicine, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK.
4
Physiological Genomics and Medicine, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK.
5
Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA.
6
Department of Pathology, University of Utah and ARUP Laboratories, Salt Lake City, UT 84108, USA.
7
Blood Center of Wisconsin, Milwaukee, WI 53213, USA.
8
Genomics Laboratory, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, London, UK.
9
National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Health, Bethesda, MD 20892, USA.
10
Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA.
11
Molecular Endocrinology Group, Department of Medicine, Imperial College London, London W12 0NN, UK.
12
Departments of Orthopaedics and Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: agnes.vignery@yale.edu.
13
Integrative Genomics and Medicine, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK. Electronic address: enrico.petretto@imperial.ac.uk.
14
Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, UK. Electronic address: jacquesb@imperial.ac.uk.

Abstract

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 Ca(2+) 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.

PMID:
25131209
PMCID:
PMC4471813
DOI:
10.1016/j.celrep.2014.07.032
[Indexed for MEDLINE]
Free PMC Article
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