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.
Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal / 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. -K. H.; Stanford, S. M.; Bottini, N.. - In: SCIENCE ADVANCES. - ISSN 2375-2548. - 6:26(2020), p. eaba4353. [10.1126/sciadv.aba4353]