The interleukin-33 receptor (ST2) is a novel therapeutic target to attenuate the progression of hemophilic arthropathy

Abstract Hemophilia A is an X-linked bleeding disorder caused by a blood clotting protein factor VIII deficiency. Patients with hemophilia develop recurrent bleeding episodes. When bleeding occurs in the joints, hemophilic arthropathy (HA) may develop, resulting in hemarthroses and joint deformation. A novel congenic mouse model of severe hemophilia A was generated using CRISPR/CRISPR-associated protein 9 targeting of exon 1 of the F8 gene (F8em1−/−) to explore changes in the bleeding and inflammation during HA. F8em1−/− mice have a high penetrance of spontaneous bleeding, with joint bleeds progressing to arthropathy. F8em1−/− mice were subjected to needle-induced damage to the knee to assess synchronized joint bleeding, and the development of HA and synovial inflammation was assessed. The synovium of injured joints of F8em1−/− mice had differential and temporal expression of inflammatory genes after injury. Pathway analysis identified upregulation of the interleukin-1 (IL-1) family cytokines, IL-1β and IL-33; and respective receptors IL-1 receptor accessory protein and T1/ST2 (ST2) in the synovium of mice after needle-induced HA. Soluble ST2 and IL-33 levels were elevated in the plasma of F8em1−/− mice in acute stages after needle injury to the joints. Dual ST2-deficient F8em1−/− mice were generated, with ST2-deficient hemophilic mice developing significantly reduced joint damage after needle injury relative to F8em1−/− mice. Using a therapeutic intervention, blocking ST2 after joint injury significantly ameliorated joint damage during HA in hemophilic mice. These studies in a new mouse model of HA identify a crucial role of ST2 in HA pathogenesis and highlight its potential as a novel therapeutic target.