Kcnn4 is a Regulator of Macrophage Multinucleation in Bone Homeostasis and Inflammatory Disease

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2014 Aug 19

PMID 25131209

Citations 32

Authors

Heeseog Kang

Audrey Kerloch

Maxime Rotival

Xiaoqing Xu

Qing Zhang

Zelpha DSouza

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

Agnes Vignery

Enrico Petretto

Jacques Behmoaras

Affiliations

Soon will be listed here.

Abstract

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.

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