Blocking Jak/STAT signalling using tofacitinib inhibits angiogenesis in experimental arthritis

Arthritis Research & Therapy

Paola Di Benedetto¹  Noemi Panzera¹  Nicolò Grazia¹  Vincenza Dolo²  Nadia Rucci³  Francesca Zazzeroni³  Antonio Maurizi³  Mauro Di Vito Nolfi³  Barbara Di Francesco³  Edoardo Alesse³  Anna Maria Teti³  Onorina Berardicurti⁴  Piero Ruscitti⁴  Paola Cipriani⁴  Francesco Ciccia⁵  Giuliana Guggino⁶  Roberto Giacomelli⁷  Luca Navarini⁷ 

[1] Clinical Pathology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy;Clinical Pathology Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy;Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy;Division of Rheumatology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy;Rheumatology Section, Department of Clinical and Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy;Rheumatology Section, Department of Internal Medicine, University of Palermo, Palermo, Italy;Unit of Rheumatology and Clinical Immunology, University of Rome “Campus Biomedico”, Rome, Italy;

关键词: Rheumatoid arthritis;    Angiogenesis;    Tofacitinib;   

DOI  :  10.1186/s13075-021-02587-8

来源: Springer

【 摘 要 】

ObjectiveDuring rheumatoid arthritis (RA), the angiogenic processes, occurring with pannus-formation, may be a therapeutic target. JAK/STAT-pathway may play a role and the aim of this work was to investigate the inhibiting role of a JAK-inhibitor, tofacitinib, on the angiogenic mechanisms occurring during RA.MethodsAfter ethical approval, JAK-1, JAK-3, STAT-1, STAT-3 and VEGF expression was evaluated on RA-synovial-tissues. In vitro, endothelial cells (ECs), stimulated with 20 ng/ml of VEGF and/or 1 μM of tofacitinib, were assessed for tube formation, migration and proliferation, by Matrigel, Boyden chamber assay and ki67 gene-expression. In vivo, 32 mice received collagen (collagen-induced arthritis (CIA)) and 32 mice PBS (control). At day 19, CIA and controls mice were divided: 16 mice receiving vehicle and 16 mice receiving tofacitinib. At day 35, the arthritis score, the thickness of paw joints and the serum levels of VEGF and Ang-2 were evaluated.ResultsThe expression of JAK-1, JAK-3, STAT-1, STAT-3 and VEGF in synovial tissue of RA-patients were significantly higher than healthy controls. In vitro, tofacitinib inhibited the ECs ability to form vessels, to proliferate and to migrate. In vivo, administration of tofacitinib prevented the increase of the arthritis score, the paw thickness, the synovial vessels and VEGF and Ang-2 serum-accumulation, when compared to CIA without tofacitinib.ConclusionsWe explored the anti-angiogenic role of tofacitinib, reporting its ability to inhibit in vitro the angiogenic mechanisms of ECs and in vivo the formation of new synovial vessels, occurring in CIA model. These findings suggest that the therapeutic effect of tofacitinib during RA may be also related to its anti-angiogenic activity.

【 授权许可】

CC BY