Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NF-κB and Interferon Signaling: Implications for Paget's Disease

Rami Obaid, Sachin E. Wani, Asim Azfer, Toby Hurd, Ruth Jones, Philip Cohen, Stuart H. Ralston, Omar Al Bagha

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28 Citations (Scopus)

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. Using mouse models, Obaid et al. identify a role of optineurin in bone metabolism as a negative regulator of osteoclast differentiation. Loss of optineurin function leads to increased bone turnover in mice, suggesting a mechanism by which genetic variants in optineurin predispose to Paget's disease of bone.

Original languageEnglish
Pages (from-to)1096-1102
Number of pages7
JournalCell Reports
Volume13
Issue number6
DOIs
Publication statusPublished - 10 Nov 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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