Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal
Open Access
- 26 June 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 6 (26), eaba4353
- https://doi.org/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.Keywords
Funding Information
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR066053)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR064194)
- Congressionally Directed Medical Research Programs (W81XWH-16-1-0751)
- Arthritis National Research Foundation (632852)
- MedImmune
- Sahlgrenska Universitetssjukhuset (C4I-2018-01-10)
- Sahlgrenska Akademin (ALFGBG-775731)
- Stiftelsen Professor Nanna Svartz Fond (2018-00251)
- Swedish Rheumatism Foundation (R-663971)
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