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

Mark R Tanner,Arielle Raugh,Christine Beeton,William K A Sikkema,Nejla Yosef,James M Tour,Carlos P Flores-Suarez,Teresina Laragione,Redwan Huq,Pércio S Gulko,Lizanne G Nilewski,Cody Schmitt

doi:10.3390/antiox9101005

Abstract

Reactive oxygen species have been involved in the pathogenesis of rheumatoid arthritis (RA). Our goal was to determine the effects of selectively scavenging superoxide (O2•−) and hydroxyl radicals with antioxidant nanoparticles, called poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs), on the pathogenic functions of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and on the progression of an animal model of RA. We used human FLS from patients with RA to determine PEG-HCC internalization and effects on FLS cytotoxicity, invasiveness, proliferation, and production of proteases. We used the pristane-induced arthritis (PIA) rat model of RA to assess the benefits of PEG-HCCs on reducing disease severity. PEG-HCCs were internalized by RA-FLS, reduced their intracellular O2•−, and reduced multiple measures of their pathogenicity in vitro, including proliferation and invasion. In PIA, PEG-HCCs caused a 65% reduction in disease severity, as measured by a standardized scoring system of paw inflammation and caused a significant reduction in bone and tissue damage, and circulating rheumatoid factor. PEG-HCCs did not induce lymphopenia during PIA. Our study demonstrated a role for O2•− and hydroxyl radicals in the pathogenesis of a rat model of RA and showed efficacy of PEG-HCCs in treating a rat model of RA.

Highlights

Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis and both immune cells and resident joint cells, such as fibroblast-like synoviocytes (FLS) participate in pathogenesis [1,2,3,4,5].Reactive oxygen species (ROS) such as superoxide (O2−) are implicated in the progression of rheumatoid arthritis (RA) [6,7,8,9]
PEG-HCCs Are Internalized by RA-FLS and Reduce the Cells’ Intracellular O2− Levels
As control FLS, we and others [39,40,41] 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]

Summary

Introduction

Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis and both immune cells and resident joint cells, such as fibroblast-like synoviocytes (FLS) participate in pathogenesis [1,2,3,4,5].Reactive oxygen species (ROS) such as superoxide (O2−) are implicated in the progression of RA [6,7,8,9]. There is an unmet need for the development of potent and O2− selective antioxidants as potential therapeutics for RA

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