Inhibition of Inflammatory Arthritis Using Fullerene Nanomaterials
Anthony L. Dellinger1, Pierre Cunin2, David Lee3, Andrew L. Kung4, D. Bradford Brooks5, Zhiguo Zhou5, Peter A. Nigrovic2, Christopher L. Kepley1* 1 University of North Carolina Greensboro, Joint School of Nanosceince and Nanoengineering, Greensboro, North Carolina, United States of America, 2 Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, and Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 3 Novartis Institutes for Biomedical Research, Basel, Switzerland, 4 Dana Farber Institute, Boston, Massachusetts, United States of America, 5 Luna Innovations Incorporated, Danville, Virginia, United States of America
Inflammatory arthritis (e.g. rheumatoid arthritis; RA) is a complex disease driven by the in- terplay 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 be- tween autoantibodies, soluble mediators, and other effector populations in inflammatory ar- thritis, 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, syno- vial 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 deriva- tives 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 stud- ies 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 ar- thritis, 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 l
ineages beyond the MC repre- sent 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.
Copyright: © 2015 Dellinger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.