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

Heeseog Kang, Audrey Kerloc'h, Maxime Rotival, Xiaoqing Xu, Qing Zhang, Zelpha D'Souza, Michael Kim, Jodi Carlson Scholz, Jeong Hun Ko, Prashant K. Srivastava, Jonathan R. Genzen, Weiguo Cui, Timothy J. Aitman, Laurence Game, James E. Melvin, Adedayo Hanidu, Janice Dimock, Jie Zheng, Donald Souza, Aruna K. BeheraGerald Nabozny, H. Terence Cook, J. H.Duncan Bassett, Graham R. Williams, Jun Li, Agnès Vignery, Enrico Petretto, Jacques Behmoaras

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Macrophages can fuse to form osteoclasts in bone ormultinucleate 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 MGCformation 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.

Original languageEnglish (US)
Pages (from-to)1210-1224
Number of pages15
JournalCell reports
Volume8
Issue number4
DOIs
StatePublished - Aug 21 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kang, H., Kerloc'h, A., Rotival, M., Xu, X., Zhang, Q., D'Souza, Z., Kim, M., Scholz, J. C., Ko, J. H., Srivastava, P. K., Genzen, J. R., Cui, W., Aitman, T. J., Game, L., Melvin, J. E., Hanidu, A., Dimock, J., Zheng, J., Souza, D., ... Behmoaras, J. (2014). Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory disease. Cell reports, 8(4), 1210-1224. https://doi.org/10.1016/j.celrep.2014.07.032