title: Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NF-κB and Interferon Signaling: Implications for Paget's Disease.
abstract: Paget's disease of bone (PDB) is a common disease characterized by osteoclast activation that leads to various skeletal complications. Susceptibility to PDB is mediated by a common variant at the optineurin (OPTN) locus, which is associated with reduced levels of mRNA. However, it is unclear how this leads to the development of PDB. Here, we show that OPTN acts as a negative regulator of osteoclast differentiation in vitro and that mice with a loss-of-function mutation in Optn have increased osteoclast activity and bone turnover. Osteoclasts derived from Optn mutant mice have an increase in NF-κB activation and a reduction in interferon beta expression in response to RANKL when compared to wild-type mice. These studies identify OPTN as a regulator of bone resorption and are consistent with a model whereby genetically determined reductions in OPTN expression predispose to PDB by enhancing osteoclast differentiation.
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Rami
authors.initials: R
authors.lastname: Obaid
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Sachin E
authors.initials: SE
authors.lastname: Wani
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Asim
authors.initials: A
authors.lastname: Azfer
authors.affiliation: Medical Research Council Human Genetic Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Toby
authors.initials: T
authors.lastname: Hurd
authors.affiliation: Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, University of Dundee, Dundee DD1 5HE, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Jones
authors.affiliation: Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, University of Dundee, Dundee DD1 5HE, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Cohen
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address: omar.albagha@ed.ac.uk.
authors.forename: Omar M E
authors.initials: OME
authors.lastname: Albagha
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002478:Cells, Cultured; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010001:Osteitis Deformans / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D005136:Eye Proteins; D026901:Membrane Transport Proteins; D016328:NF-kappa B; C501288:Optn protein, mouse; D053245:RANK Ligand; D016899:Interferon-beta