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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis / metabolism*
  • Arthritis / pathology
  • Bone Resorption / metabolism
  • Bone and Bones / immunology
  • Bone and Bones / metabolism*
  • Calcium Signaling
  • Cell Nucleus / physiology*
  • Cells, Cultured
  • Gene Regulatory Networks
  • Glomerulonephritis / immunology
  • Glomerulonephritis / metabolism*
  • Homeostasis
  • Humans
  • Intermediate-Conductance Calcium-Activated Potassium Channels / physiology*
  • Macrophages / metabolism*
  • Mice, Knockout
  • Rats, Inbred Lew
  • Rats, Inbred WKY
  • Receptors, Immunologic / metabolism


  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • Kcnn4 protein, rat
  • Receptors, Immunologic