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Svensson MND, Zoccheddu M, Yang S, et al. Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal. Sci Adv. 2020;6(26):eaba4353doi: 10.1126/sciadv.aba4353.
Svensson, M. N. D., Zoccheddu, M., Yang, S., Nygaard, G., Secchi, C., Doody, K. M., Slowikowski, K., Mizoguchi, F., Humby, F., Hands, R., Santelli, E., Sacchetti, C., Wakabayashi, K., Wu, D. J., Barback, C., Ai, R., Wang, W., Sims, G. P., Mydel, P., Kasama, T., Boyle, D. L., Galimi, F., Vera, D., Tremblay, M. L., Raychaudhuri, S., Brenner, M. B., Firestein, G. S., Pitzalis, C., Ekwall, A. H., Stanford, S. M., & Bottini, N. (2020). Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal. Science advances, 6(26), eaba4353. https://doi.org/10.1126/sciadv.aba4353
Svensson, Mattias N D, et al. "Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal." Science advances vol. 6,26 (2020): eaba4353. doi: https://doi.org/10.1126/sciadv.aba4353
Svensson MND, Zoccheddu M, Yang S, Nygaard G, Secchi C, Doody KM, Slowikowski K, Mizoguchi F, Humby F, Hands R, Santelli E, Sacchetti C, Wakabayashi K, Wu DJ, Barback C, Ai R, Wang W, Sims GP, Mydel P, Kasama T, Boyle DL, Galimi F, Vera D, Tremblay ML, Raychaudhuri S, Brenner MB, Firestein GS, Pitzalis C, Ekwall AH, Stanford SM, Bottini N. Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal. Sci Adv. 2020 Jun 26;6(26):eaba4353. doi: 10.1126/sciadv.aba4353. eCollection 2020 Jun. PMID: 32637608; PMCID: PMC7319753.
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Sci Adv. 2020 Jun 26;6(26):eaba4353. doi: 10.1126/sciadv.aba4353. eCollection 2020 Jun.

Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal.

Science advances

Mattias N D Svensson, Martina Zoccheddu, Shen Yang, Gyrid Nygaard, Christian Secchi, Karen M Doody, Kamil Slowikowski, Fumitaka Mizoguchi, Frances Humby, Rebecca Hands, Eugenio Santelli, Cristiano Sacchetti, Kuninobu Wakabayashi, Dennis J Wu, Christopher Barback, Rizi Ai, Wei Wang, Gary P Sims, Piotr Mydel, Tsuyoshi Kasama, David L Boyle, Francesco Galimi, David Vera, Michel L Tremblay, Soumya Raychaudhuri, Michael B Brenner, Gary S Firestein, Costantino Pitzalis, Anna-Karin H Ekwall, Stephanie M Stanford, Nunzio Bottini

Affiliations

  1. Department of Medicine, Altman Clinical and Translational Research Institute, University of California, San Diego, La Jolla, CA 92093, USA.
  2. Division of Cellular Biology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  3. Department of Biomedical Sciences, National Institute of Biostructures and Biosystems, University of Sassari Medical School, 07100 Sassari, Italy.
  4. Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  5. Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  6. Partners HealthCare Personalized Medicine, Boston, MA 02115, USA.
  7. Program in Medical and Population Genetics, Broad Institute of Massachusetts Technical Institute and Harvard University, Cambridge, MA 02138, USA.
  8. Bioinformatics and Integrative Genomics, Harvard University, Cambridge, MA 02138, USA.
  9. Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8519, Japan.
  10. Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
  11. Division of Rheumatology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
  12. Department of Radiology, University of California, La Jolla, CA 92093, USA.
  13. UCSD Molecular Imaging Program, University of California, La Jolla, CA 92093, USA.
  14. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  15. Respiratory, Inflammation and Autoimmunity, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.
  16. Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, The Laboratory Building, 5th Floor, 5021 Bergen, Norway.
  17. Department of Microbiology, Jagiellonian University, Kraków, Poland.
  18. Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.
  19. Department of Biochemistry, McGill University, Montréal, Québec H3A 1A3, Canada.
  20. Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada.
  21. Rheumatology Unit, Karolinska Institutet, Stockholm S-171 76, Sweden.
  22. Institute of Inflammation and Repair, University of Manchester, Manchester M13 9PT, UK.
  23. Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  24. Centre for Bone and Arthritis Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

PMID: 32637608 PMCID: PMC7319753 DOI: 10.1126/sciadv.aba4353

Abstract

Fibroblast-like synoviocytes (FLS) are joint-lining cells that promote rheumatoid arthritis (RA) pathology. Current disease-modifying antirheumatic agents (DMARDs) operate through systemic immunosuppression. FLS-targeted approaches could potentially be combined with DMARDs to improve control of RA without increasing immunosuppression. Here, we assessed the potential of immunoglobulin-like domains 1 and 2 (Ig1&2), a decoy protein that activates the receptor tyrosine phosphatase sigma (PTPRS) on FLS, for RA therapy. We report that PTPRS expression is enriched in synovial lining RA FLS and that Ig1&2 reduces migration of RA but not osteoarthritis FLS. Administration of an Fc-fusion Ig1&2 attenuated arthritis in mice without affecting innate or adaptive immunity. Furthermore, PTPRS was down-regulated in FLS by tumor necrosis factor (TNF) via a phosphatidylinositol 3-kinase-mediated pathway, and TNF inhibition enhanced PTPRS expression in arthritic joints. Combination of ineffective doses of TNF inhibitor and Fc-Ig1&2 reversed arthritis in mice, providing an example of synergy between FLS-targeted and immunosuppressive DMARD therapies.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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