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

• Susceptibility to Paget's disease is associated with reduced optineurin expression
• Optineurin knockdown enhances osteoclast differentiation
• Loss of optineurin function increases bone turnover in vivo
• Optineurin inhibits osteoclast formation by modulating NF-κB and IFN-β signaling

SummaryPaget’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.

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