Section C Project C06

Role of type I interferon in inflammatory bone disease

Gain-of-function mutations in IFIH1 encoding the RNA sensor MDA5 underlie Singleton-Merten syndrome, an interferonopathy characterized by psoriasis, osteopenia, acroosteolysis, periodontitis and vascular calcification. MDA5 recognizes pathogen-derived dsRNA and signals via MAVS/IRF3 to activate type I interferon (IFN). Notably, MDA5 expression is also induced in FLS from RA patients and associated with a proinflammatory phenotype. The mechanisms, by which unabated type I IFN drives inflammatory bone loss remains largely undefined. Primary fibroblasts from patients with IFIH1 mutations secrete large amounts of VEGF, a major regulator of bone, suggesting a previously unappreciated link between type I IFN and VEGF in bone homeostasis. The aim of this project is to gain mechanistic insight into type I IFN-mediated inflammatory bone disease and to pinpoint novel pathways that can be targeted for therapeutic intervention.