%0 Journal Article
%T Global deletion of Optineurin results in altered type I IFN signaling and abnormal bone remodeling in a model of Paget¡¯s disease
%J -
%D 2019
%R https://doi.org/10.1038/s41418-019-0341-6
%X Genome-wide association studies (GWAS) have identified Optineurin (OPTN) as genetically linked to Paget¡¯s disease of the bone (PDB), a chronic debilitating bone remodeling disorder characterized by localized areas of increased bone resorption and abnormal bone remodeling. However, only ~10% of mouse models with a mutation in Optn develop PDB, thus hindering the mechanistic understanding of the OPTN-PDB axis. Here, we reveal that 100% of aged Optn global knockout (Optn£¿/£¿) mice recapitulate the key clinical features observed in PDB patients, including polyostotic osteolytic lesions, mixed-phase lesions, and increased serum levels of alkaline phosphatase (ALP). Differentiation of primary osteoclasts ex vivo revealed that the absence of Optn resulted in an increased osteoclastogenesis. Mechanistically, Optn-deficient osteoclasts displayed a significantly decreased type I interferon (IFN) signature, resulting from both defective production of IFN¦Â and impaired signaling via the IFN¦Á/¦ÂR, which acts as a negative feedback loop for osteoclastogenesis and survival. These data highlight the dual roles of OPTN in the type I IFN response to restrain osteoclast activation and bone resorption, offering a novel therapeutic target for PDB. Therefore, our study describes a novel and essential mouse model for PDB and define a key role for OPTN in osteoclast differentiation
%U https://www.nature.com/articles/s41418-019-0341-6