Th17 lymphocyte‐dependent degradation of joint cartilage by synovial fibroblasts in a humanized mouse model of arthritis and reversal by secukinumab

• Published in: European journal of immunology Vol. 51; no. 1; pp. 220 - 230
• Main Authors: Margheri, Francesca, Maggi, Laura, Biagioni, Alessio, Chillà, Anastasia, Laurenzana, Anna, Bianchini, Francesca, Bani, Daniele, Capone, Manuela, Mazzoni, Alessio, Rossi, Maria Caterina, Liotta, Francesco, Cosmi, Lorenzo, Giani, Teresa, Cimaz, Rolando, Fibbi, Gabriella, Annunziato, Francesco, Del Rosso, Mario
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.01.2021
• Subjects: Adolescent; Animal models; Animals; Antibodies, Monoclonal, Humanized - therapeutic use; Arthritis; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Arthritis, Experimental - therapy; Arthritis, Juvenile - immunology; Arthritis, Juvenile - pathology; Arthritis, Juvenile - therapy; Cartilage; Cartilage (articular); Cartilage degradation; Cartilage, Articular - immunology; Cartilage, Articular - metabolism; Cartilage, Articular - pathology; Case-Control Studies; Child; Child, Preschool; Collagen; Cytokines; Cytokines - immunology; Degradation; Disease Models, Animal; Fibroblasts; Fibroblasts - immunology; Fibroblasts - metabolism; Fibroblasts - pathology; Gelatinase A; Gelatinase B; Helper cells; Humans; In Vitro Techniques; Interleukin-17 - antagonists & inhibitors; Juvenile idiopathic arthritis; Lymphocytes; Lymphocytes T; Mice; Mice, SCID; Monoclonal antibodies; Peripheral blood; Phenotypes; Proteolysis; Synovial fibroblasts; Synovial fluid; Synovial Membrane - immunology; Synovial Membrane - metabolism; Synovial Membrane - pathology; Th17 Cells - immunology; Th17 Cells - pathology; Thrombolytic drugs; T‐helper lymphocytes; U-Plasminogen activator; Synovial fibroblasts; Cartilage degradation; T-helper lymphocytes; Juvenile idiopathic arthritis
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.202048773

How T‐helper (Th) lymphocyte subpopulations identified in synovial fluid from patients with juvenile idiopathic arthritis (JIA) (Th17, classic Th1, or nonclassic Th1) drive joint damage is of great interest for the possible use of biological drugs that inhibit the specific cytokines. Our objective was to clarify the role of such Th subpopulations in the pathogenesis of articular cartilage destruction by synovial fibroblasts (SFbs), and the effect of Th17 blockage in an animal model. SFbs were isolated from healthy subjects and patients with JIA, and peripheral blood Th lymphocytes subsets were obtained from healthy subjects. Fragments of human cartilage from healthy subjects in a collagen matrix containing JIA or normal SFbs grafted underskin in SCID mice were used to measure cartilage degradation under the effects of Th supernatants. JIA SFbs overexpress MMP9 and MMP2 and Th17 induce both MMPs in normal SFbs, while nonclassic Th1 upregulate urokinase plasminogen activator (uPA) activity. In vitro invasive phenotype of normal SFbs is stimulated with conditioned medium of Th17 and nonclassic‐Th1. In the in vivo “inverse wrap” model, normal SFbs stimulated with supernatants of Th17‐lymphocytes and nonclassic Th1 produced a cartilage invasion and degradation similar to JIA SFbs. Secukinumab inhibits the cartilage damage triggered by factors produced by Th17. Normal SFbs stimulated with supernatants of activated Th17 lymphocytes produce a MMP9‐dependent cartilage degradation in the in vivo mouse model, similar to JIA. Secukinumab inhibits IL17‐mediated MMP9 production, paving the way for the use of biological drugs capable of blocking protease activity in JIA.