Centre for Inflammatory Disease, Department of Immunology and Inflammation, Hammersmith Hospital, Imperial College London, London, United Kingdom; Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United Kingdom
Jeong-Hun Ko
Centre for Inflammatory Disease, Department of Immunology and Inflammation, Hammersmith Hospital, Imperial College London, London, United Kingdom; Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United Kingdom
John Logan
Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United Kingdom
Hayley Protheroe
Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United Kingdom
Kee-Beom Kim
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States
Amelia Li Min Tan
Duke-NUS Medical School, Singapore, Singapore
Peter I Croucher
The Garvan Institute of Medical Research and St. Vincent's Clinical School, University of NewSouth Wales Medicine, Sydney, Australia
Kwon-Sik Park
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States
Maxime Rotival
Human Evolutionary Genetics Unit, Institut Pasteur, Centre National de la Recherche Scientifique, UMR 2000, Paris, France
Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United Kingdom
Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United Kingdom
Jacques Behmoaras
Centre for Inflammatory Disease, Department of Immunology and Inflammation, Hammersmith Hospital, Imperial College London, London, United Kingdom
Functional characterisation of cell-type-specific regulatory networks is key to establish a causal link between genetic variation and phenotype. The osteoclast offers a unique model for interrogating the contribution of co-regulated genes to in vivo phenotype as its multinucleation and resorption activities determine quantifiable skeletal traits. Here we took advantage of a trans-regulated gene network (MMnet, macrophage multinucleation network) which we found to be significantly enriched for GWAS variants associated with bone-related phenotypes. We found that the network hub gene Bcat1 and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global (Pik3cb-/-, Atp8b2+/-, Igsf8-/-, Eml1-/-, Appl2-/-, Deptor-/-) and myeloid-specific Slc40a1 knockout mice displayed abnormal bone phenotypes. We report opposing effects of MMnet genes on bone mass in mice and osteoclast multinucleation/resorption in humans with strong correlation between the two. These results identify MMnet as a functionally conserved network that regulates osteoclast multinucleation and bone mass.
