Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory disease. Cell Rep 2014 Aug 21;8(4):1210-24
Date
08/19/2014Pubmed ID
25131209Pubmed Central ID
PMC4471813DOI
10.1016/j.celrep.2014.07.032Scopus ID
2-s2.0-84908355965 (requires institutional sign-in at Scopus site) 46 CitationsAbstract
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.
Author List
Kang H, Kerloc'h A, Rotival M, Xu X, Zhang Q, D'Souza Z, Kim M, Scholz JC, Ko JH, Srivastava PK, Genzen JR, Cui W, Aitman TJ, Game L, Melvin JE, Hanidu A, Dimock J, Zheng J, Souza D, Behera AK, Nabozny G, Cook HT, Bassett JH, Williams GR, Li J, Vignery A, Petretto E, Behmoaras JMESH terms used to index this publication - Major topics in bold
AnimalsArthritis
Bone Resorption
Bone and Bones
Calcium Signaling
Cell Nucleus
Cells, Cultured
Gene Regulatory Networks
Glomerulonephritis
Homeostasis
Humans
Intermediate-Conductance Calcium-Activated Potassium Channels
Macrophages
Mice, Knockout
Rats, Inbred Lew
Rats, Inbred WKY
Receptors, Immunologic
