Abstract
Inflammatory arthritis (e.g. rheumatoid arthritis; RA) is a complex disease driven by the interplay of multiple cellular lineages. Fullerene derivatives have previously been shown to have anti-inflammatory capabilities mediated, in part, by their ability to prevent inflammatory mediator release by mast cells (MC). Recognizing that MC can serve as a cellular link between autoantibodies, soluble mediators, and other effector populations in inflammatory arthritis, it was hypothesized that fullerene derivatives might be used to target this inflammatory disease. A panel of fullerene derivatives was tested for their ability to affect the function of human skin-derived MC as well as other lineages implicated in arthritis, synovial fibroblasts and osteoclasts. It is shown that certain fullerene derivatives blocked FcγR- and TNF-α-induced mediator release from MC; TNF-α-induced mediator release from RA synovial fibroblasts; and maturation of human osteoclasts. MC inhibition by fullerene derivatives was mediated through the reduction of mitochondrial membrane potential and FcγR-mediated increases in cellular reactive oxygen species and NF-κB activation. Based on these in vitro data, two fullerene derivatives (ALM and TGA) were selected for in vivo studies using K/BxN serum transfer arthritis in C57BL/6 mice and collagen-induced arthritis (CIA) in DBA/1 mice. Dye-conjugated fullerenes confirmed localization to affected joints in arthritic animals but not in healthy controls. In the K/BxN moldel, fullerenes attenuated arthritis, an effect accompanied by reduced histologic inflammation, cartilage/bone erosion, and serum levels of TNF-α. Fullerenes remained capable of attenuating K/BxN arthritis in mast cell-deficient mice Cre-Master mice, suggesting that lineages beyond the MC represent relevant targets in this system. These studies suggest that fullerene derivatives may hold promise both as an assessment tool and as anti-inflammatory therapy of arthritis.
Highlights
Oxygen metabolism has an important role in the pathogenesis of inflammatory arthritis and therapies that target its dysregulation have been investigated as potential treatments
Our results suggest rationally designed fullerene derivatives may provide an effective therapeutic option for the treatment of inflammatory arthritis by targeting Reactive oxygen species (ROS) to prevent stimulation of pro-inflammatory cytokines, osteoclast formation, and stabilizing critical cells involved in rheumatoid arthritis (RA) progression
Fullerene derivatives inhibit critical parameters important for the pathologies associated with inflammatory arthritis as assessed by in vitro models
Summary
Oxygen metabolism has an important role in the pathogenesis of inflammatory arthritis and therapies that target its dysregulation have been investigated as potential treatments. Reactive oxygen species produced in the course of cellular oxidative phosphorylation, and by activated phagocytic cells during oxidative bursts, exceed the physiological buffering capacity and result in oxidative stress [1,2]. Various forms of antioxidant therapy have demonstrated promising results in experimental arthritis models [3,4,5,6,7]. The polyphenolic fraction of green tea containing potent antioxidants ameliorates collagen-induced arthritis [8]. Carvedilol, an adrenergic antagonist with antioxidant/ anti-inflammatory properties effectively suppressed inflammation in two arthritis models [3]
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