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.