Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal
Svensson, Mattias N.D.; Zoccheddu, Martina; Yang, Shen; Nygaard, Gyrid; Secchi, Christian; Doody, Karen M.; Slowikowski, Kamil; Mizoguchi, Fumitaka; Humby, Frances; Hands, Rebecca; Santelli, Eugenio; Sacchetti, Cristiano; Wakabayashi, Kuninobu; Wu, Dennis J.; Barback, Christopher; Ai, Rizi; Wang, Wei; Sims, Gary P.; Mydel, Piotr Mateusz; Kasama, Tsuyoshi; Boyle, David L.; Galimi, Francesco; Vera, David; Tremblay, Michel L.; Raychaudhuri, Soumya; Brenner, Michael B.; Firestein, Gary S.; Pitzalis, Costantino; Ekwall, Anna-Karin H.; Stanford, Stephanie M.; Bottini, Nunzio
Journal article, Peer reviewed
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Original versionScience Advances. 2020, 6 (26), eaba4353 10.1126/sciadv.aba4353
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.