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. Behera; Gerald Nabozny; H. Terence Cook; J. H.Duncan Bassett; Graham R. Williams; Jun Li; Agnès Vignery; Enrico Petretto; Jacques Behmoaras

doi:10.1016/j.celrep.2014.07.032

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

^*Corresponding author for this work

Pathology

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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 language	English (US)
Pages (from-to)	1210-1224
Number of pages	15
Journal	Cell reports
Volume	8
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2014.07.032
State	Published - Aug 21 2014

Funding

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\u2019s Seventh Framework Programme (FP7/2007\u20132013) 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.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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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

@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",

}

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, JHD, Williams, GR, Li, J, Vignery, A, Petretto, E & Behmoaras, J 2014, 'Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory disease', Cell reports, vol. 8, no. 4, pp. 1210-1224. https://doi.org/10.1016/j.celrep.2014.07.032

TY - JOUR

T1 - Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory disease

AU - Kang, Heeseog

AU - Kerloc'h, Audrey

AU - Rotival, Maxime

AU - Xu, Xiaoqing

AU - Zhang, Qing

AU - D'Souza, Zelpha

AU - Kim, Michael

AU - Scholz, Jodi Carlson

AU - Ko, Jeong Hun

AU - Srivastava, Prashant K.

AU - Genzen, Jonathan R.

AU - Cui, Weiguo

AU - Aitman, Timothy J.

AU - Game, Laurence

AU - Melvin, James E.

AU - Hanidu, Adedayo

AU - Dimock, Janice

AU - Zheng, Jie

AU - Souza, Donald

AU - Behera, Aruna K.

AU - Nabozny, Gerald

AU - Cook, H. Terence

AU - Bassett, J. H.Duncan

AU - Williams, Graham R.

AU - Li, Jun

AU - Vignery, Agnès

AU - Petretto, Enrico

AU - Behmoaras, Jacques

N1 - 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’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.

PY - 2014/8/21

Y1 - 2014/8/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84908355965&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908355965&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2014.07.032

DO - 10.1016/j.celrep.2014.07.032

M3 - Article

C2 - 25131209

AN - SCOPUS:84908355965

SN - 2211-1247

VL - 8

SP - 1210

EP - 1224

JO - Cell reports

JF - Cell reports

IS - 4

ER -

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

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