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Global deletion of Optineurin results in altered type I IFN signaling and abnormal bone remodeling in a model of Paget’s disease

Abstract

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 IFNβ and impaired signaling via the IFNα/βR, 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.

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Acknowledgements

We would like to thank Danielle Callaway of the University of Texas, Brendan Boyce of the University of Rochester, and Kim Mansky of University of Minnesota for their help on osteoclast primary culture. We thank the staff in Biomedical Research Imaging Center and Maya Styner at University of North Carolina for their imaging technical support. We also thank Kevin Gerrish and Rick Fannin in the Molecular Genomics Core at the National Institute of Environmental Health Sciences for microarray support. We also thank Michael Fessler (NIEHS), Donald N. Cook (NIEHS), Kevin Byrd (UNC School of Dentistry), and Richard Loeser (UNC School of Medicine) for their careful assistance with this manuscript. This work was supported in part by the NIH Intramural Research Program 1ZIAES10328601 (to J.M.), NIH/NIDCR R01DE022816 (to C.K.) and R90DE022527 (to SW.W.), Butler Pioneer Award (to H.T.), Alcon Research Institute (to H.T.), American Glaucoma Society (to H.T.), K08-EY021520 (to H.T.), and NEI core grant P30-EY005722 (to Duke Eye Center).

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Correspondence to Jennifer Martinez.

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