title: Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory disease.
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.
authors.affiliation: Departments of Orthopaedics and Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Heeseog
authors.initials: H
authors.lastname: Kang
authors.affiliation: Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, UK.
authors.forename: Audrey
authors.initials: A
authors.lastname: Kerloc'h
authors.affiliation: Integrative Genomics and Medicine, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK.
authors.forename: Maxime
authors.initials: M
authors.lastname: Rotival
authors.affiliation: Departments of Orthopaedics and Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Xu
authors.affiliation: Departments of Orthopaedics and Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Physiological Genomics and Medicine, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK.
authors.forename: Zelpha
authors.initials: Z
authors.lastname: D'Souza
authors.affiliation: Departments of Orthopaedics and Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kim
authors.affiliation: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Jodi Carlson
authors.initials: JC
authors.lastname: Scholz
authors.affiliation: Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, UK.
authors.forename: Jeong-Hun
authors.initials: JH
authors.lastname: Ko
authors.affiliation: Integrative Genomics and Medicine, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK.
authors.forename: Prashant K
authors.initials: PK
authors.lastname: Srivastava
authors.affiliation: Department of Pathology, University of Utah and ARUP Laboratories, Salt Lake City, UT 84108, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Genzen
authors.affiliation: Blood Center of Wisconsin, Milwaukee, WI 53213, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Cui
authors.affiliation: Physiological Genomics and Medicine, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Aitman
authors.affiliation: Genomics Laboratory, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, London, UK.
authors.forename: Laurence
authors.initials: L
authors.lastname: Game
authors.affiliation: National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Melvin
authors.affiliation: Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA.
authors.forename: Adedayo
authors.initials: A
authors.lastname: Hanidu
authors.affiliation: Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Dimock
authors.affiliation: Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Souza
authors.affiliation: Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA.
authors.forename: Aruna K
authors.initials: AK
authors.lastname: Behera
authors.affiliation: Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Nabozny
authors.affiliation: Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, UK.
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.affiliation: Molecular Endocrinology Group, Department of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: J H Duncan
authors.initials: JH
authors.lastname: Bassett
authors.affiliation: Molecular Endocrinology Group, Department of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Williams
authors.affiliation: Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Departments of Orthopaedics and Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: agnes.vignery@yale.edu.
authors.forename: Agnès
authors.initials: A
authors.lastname: Vignery
authors.affiliation: Integrative Genomics and Medicine, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK. Electronic address: enrico.petretto@imperial.ac.uk.
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
authors.affiliation: Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, UK. Electronic address: jacquesb@imperial.ac.uk.
authors.forename: Jacques
authors.initials: J
authors.lastname: Behmoaras
mesh_terms: D000818:Animals; D001168:Arthritis / Q000378:metabolism* / Q000473:pathology; D001862:Bone Resorption / Q000378:metabolism; D001842:Bone and Bones / Q000276:immunology / Q000378:metabolism*; D020013:Calcium Signaling; D002467:Cell Nucleus / Q000502:physiology*; D002478:Cells, Cultured; D053263:Gene Regulatory Networks; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D018345:Mice, Knockout; D011917:Rats, Inbred Lew; D011921:Rats, Inbred WKY; D011971:Receptors, Immunologic / Q000378:metabolism
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C491575:Kcnn4 protein, rat; D011971:Receptors, Immunologic