Cell Reports (Aug 2014)
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
Affiliations
- Heeseog Kang
- Departments of Orthopaedics and Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA
- Audrey Kerloc’h
- Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, UK
- Maxime Rotival
- Integrative Genomics and Medicine, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK
- Xiaoqing Xu
- Departments of Orthopaedics and Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA
- Qing Zhang
- Departments of Orthopaedics and Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA
- Zelpha D’Souza
- Physiological Genomics and Medicine, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK
- Michael Kim
- Departments of Orthopaedics and Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA
- Jodi Carlson Scholz
- Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA
- Jeong-Hun Ko
- Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, UK
- Prashant K. Srivastava
- Integrative Genomics and Medicine, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK
- Jonathan R. Genzen
- Department of Pathology, University of Utah and ARUP Laboratories, Salt Lake City, UT 84108, USA
- Weiguo Cui
- Blood Center of Wisconsin, Milwaukee, WI 53213, USA
- Timothy J. Aitman
- Physiological Genomics and Medicine, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK
- Laurence Game
- Genomics Laboratory, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, London, UK
- James E. Melvin
- National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Health, Bethesda, MD 20892, USA
- Adedayo Hanidu
- Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA
- Janice Dimock
- Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA
- Jie Zheng
- Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA
- Donald Souza
- Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA
- Aruna K. Behera
- Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA
- Gerald Nabozny
- Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA
- H. Terence Cook
- Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, UK
- J.H. Duncan Bassett
- Molecular Endocrinology Group, Department of Medicine, Imperial College London, London W12 0NN, UK
- Graham R. Williams
- Molecular Endocrinology Group, Department of Medicine, Imperial College London, London W12 0NN, UK
- Jun Li
- Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA
- Agnès Vignery
- Departments of Orthopaedics and Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA
- Enrico Petretto
- Integrative Genomics and Medicine, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK
- Jacques Behmoaras
- Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, UK
- DOI
- https://doi.org/10.1016/j.celrep.2014.07.032
- Journal volume & issue
-
Vol. 8,
no. 4
pp. 1210 – 1224
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 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.
