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

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

Science advances (2020-07-09)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid, ≥97.0% (CHN)
Sigma-Aldrich
Bay 11-7085, ≥98% (HPLC), solid
Sigma-Aldrich
Toluidine Blue, 8.74% (ZN (THEORY)), for microscopy (Hist., Vit.)
Sigma-Aldrich
Copper(II) 5,9,14,18,23,27,32,36-octabutoxy-2,3-naphthalocyanine, Dye content 90 %