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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Wong, S-W; Huang, B-W; Hu, X; Ho Kim, E; Kolb, JP; Padilla, RJ; Xue, P; Wang, L; Oguin, TH; Miguez, PA; Tseng, HC; Ko, C-C; Martinez, J

Published Date

  • January 2020

Published In

Volume / Issue

  • 27 / 1

Start / End Page

  • 71 - 84

PubMed ID

  • 31076632

Pubmed Central ID

  • PMC7205997

Electronic International Standard Serial Number (EISSN)

  • 1476-5403

Digital Object Identifier (DOI)

  • 10.1038/s41418-019-0341-6


  • eng

Conference Location

  • England