| First Author | Wong SW | Year | 2020 |
| Journal | Cell Death Differ | Volume | 27 |
| Issue | 1 | Pages | 71-84 |
| PubMed ID | 31076632 | Mgi Jnum | J:302744 |
| Mgi Id | MGI:6509710 | Doi | 10.1038/s41418-019-0341-6 |
| Citation | Wong SW, et al. (2020) Global deletion of Optineurin results in altered type I IFN signaling and abnormal bone remodeling in a model of Paget's disease. Cell Death Differ 27(1):71-84 |
| abstractText | 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 IFNbeta and impaired signaling via the IFNalpha/betaR, 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. |
