@article{826cb7ce12554fcc9bd32b527d9ea880,
title = "Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory disease",
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.",
author = "Heeseog Kang and Audrey Kerloc'h and Maxime Rotival and Xiaoqing Xu and Qing Zhang and Zelpha D'Souza and Michael Kim and Scholz, {Jodi Carlson} and Ko, {Jeong Hun} and Srivastava, {Prashant K.} and Genzen, {Jonathan R.} and Weiguo Cui and Aitman, {Timothy J.} and Laurence Game and Melvin, {James E.} and Adedayo Hanidu and Janice Dimock and Jie Zheng and Donald Souza and Behera, {Aruna K.} and Gerald Nabozny and Cook, {H. Terence} and Bassett, {J. H.Duncan} and Williams, {Graham R.} and Jun Li and Agn{\`e}s Vignery and Enrico Petretto and Jacques Behmoaras",
note = "Funding Information: The authors are grateful to Veterinary Clinical Services at the Yale School of Medicine and to the Yale Core Center for Musculoskeletal Diseases, in particular, to Nancy Troiano for her assistance in processing the mouse bones for histomorphometry analysis. We also thank Bolder Biopath (Boulder, CO) for processing the arthritic mouse bones for histology, and grading the pathology. We would like to thank Jennifer Smith for her excellent technical assistance and Kathrin Saar (MDC, Berlin) for genotyping protocols and data analysis. We gratefully acknowledge funding from Kidney Research UK (RP9/2013) (J.B.), Wellcome Trust (WT092523MA) (J.B.). We also acknowledge funding from the European Community{\textquoteright}s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. HEALTH-F4- 2010-241504 (EURATRANS) (E.P. and M.R.) and the Medical Research Council (E.P.). A.H., J.D., J.Z., D.S., A.K.B., G.N., and J.L. are employees of Boehringer Ingelheim. This work was supported in part by a grant from Boehringer Ingelheim. ",
year = "2014",
month = aug,
day = "21",
doi = "10.1016/j.celrep.2014.07.032",
language = "English (US)",
volume = "8",
pages = "1210--1224",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}