Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal

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.

Antioxidant Carbon Nanoparticles Inhibit Fibroblast-Like Synoviocyte Invasiveness and Reduce Disease Severity in a Rat Model of Rheumatoid Arthritis

“…However, healthy individuals do not undergo therapeutic joint surgery, it is therefore difficult to obtain healthy FLS. As control FLS, we and others [ 39 , 40 , 41 ] therefore use FLS from patients with osteoarthritis (OA) which are less aggressive than RA-FLS in terms of migration, invasiveness, and production of cytokine, chemokines and growth factors [ 42 , 43 ]. Concentrations of 10 μg/mL PEG-HCCs and higher induce the death of both RA-FLS and OA-FLS ( Figure 1 C).…”

Identification of Compounds With Glucocorticoid Sparing Effects on Suppression of Chemokine and Cytokine Production by Rheumatoid Arthritis Fibroblast-Like Synoviocytes

“…Other agents have been reported to reduce inflammation in models of arthritis that are insufficient alone, but utilize a complementary pathway that favorably modulates the activity of a known therapeutic agent. For example, the receptor tyrosine phosphatase sigma (PTPRS) activating decoy protein attenuated severity of arthritis when combined with low dose of a TNF inhibitor ( Svensson et al, 2020 ), but was insufficient in itself to have an effect. In addition, we have reported that the combination of an inhibitor of cell proliferation and a TNF inhibitor exerted synergistic effects without reducing immune responses ( Hosoya et al, 2016 ).…”

Eotaxin-1/CCL11 is involved in cell migration in rheumatoid arthritis

“…CCL11, CCR3, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) primers were purchased from Qiagen. Quantitative PCR was performed using SYBR Green quantitative PCR master mix (Qiagen) on a C1000 thermal cycler (Bio Rad, Hercules, CA, USA) as described previously 5 . The efficiency of the primer assays was guaranteed by the manufacturer to be > 90%.…”

“…RA FLS also contribute to the inflammation through the secretion of cytokines and chemokines which induce and maintain the inflammatory cells, including infiltrating lymphocytes and monocytes. It has been suggested that combination of agents selectively targeting RA FLS and current disease-modifying anti-rheumatic drugs is an option for therapy to improve disease control without increasing the risk of infection 3 – 5 .…”