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

• A CRISPR/Cas9 targeted mouse model of Haemophilia A develops spontaneous bleeds in the joints and arthropathy.

• The IL-33 receptor ST2 is a therapeutic target for haemophilic arthropathy.

Haemophilia A is an X-linked bleeding disorder caused by a blood clotting protein factor VIII deficiency. Patients with haemophilia develop recurrent bleeding episodes. When bleeding occurs in the joints, haemophilic arthropathy (HA) may develop, resulting in hemarthroses and joint deformation. A novel congenic mouse model of severe haemophilia A was generated using CRISPR/Cas9 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 synchronised 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 IL-1 family cytokines, IL-1b and IL-33, and respective receptors IL-1RAP 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 haemophilic mice developing significantly reduced joint damage after needle injury relative to F8em1-/- mice. Using a therapeutic intervention, blocking ST2 following joint injury significantly ameliorated joint damage during HA in haemophilic 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.