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

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.

• Authors: 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
• Journal: Science advances (Sci Adv) Vol. 6 Issue 26 Pg. eaba4353 (06 2020) ISSN: 2375-2548 [Electronic] United States
• PMID: 32637608 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: 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).

Chemical References

• Antirheumatic Agents
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Antirheumatic Agents (therapeutic use)
• Arthritis, Rheumatoid
• Cells, Cultured
• Fibroblasts (metabolism)
• Mice
• Synoviocytes (metabolism, pathology)
• Tumor Necrosis Factor-alpha (metabolism)