The interleukin-33 receptor (ST2) is a novel therapeutic target to attenuate the progression of hemophilic arthropathy
Abstract
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.
Article Details
Authors (20)
Heike C. Hawerkamp
1Clinical Medicine, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
Aoife Yeow
1Clinical Medicine, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
Ciara M. Byrne
1Clinical Medicine, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
Anne Chevalier
1Clinical Medicine, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
Laura Matarazzo
1Clinical Medicine, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
Alexander Lawrence
1Clinical Medicine, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
Daniel Ivers
1Clinical Medicine, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
Tatenda Murangi
1Clinical Medicine, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
Niamh O’Dowd
1Clinical Medicine, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
Anne-Marije Hulshof
2Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Ferdows Atiq
2Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Jamie M. O'Sullivan
2Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Vincent P. Kelly
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin
Conor M. Finlay
4Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
Henry J. McSorley
5Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
Bagirath Gangadharan
6Baxalta Innovations GmbH, a Member of the Takeda Group of Companies, Vienna, Austria
Birgit M. Reipert
6Baxalta Innovations GmbH, a Member of the Takeda Group of Companies, Vienna, Austria
James S. O'Donnell
2Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Peter L. Turecek
6Baxalta Innovations GmbH, a Member of the Takeda Group of Companies, Vienna, Austria
Padraic G. Fallon