Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal
Mattias N. D. Svensson, Martina Zoccheddu, Shen K. 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 V. Barback, Rizi Ai, Wei Wang, Gary P. Sims, Piotr Mydel, Tsuyoshi Kasama, David L. Boyle, Francesco Galimi, David R. Vera, Michel L. Tremblay, Soumya Raychaudhuri, Michael B. Brenner, Gary S. Firestein, Costantino Pitzalis, Anna‐Karin Hultgård Ekwall, Stephanie M. Stanford, Nunzio Bottini
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.