title: Inhibition of inflammatory arthritis using fullerene nanomaterials.
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.
authors: University of North Carolina Greensboro, Joint School of Nanosceince and Nanoengineering, Greensboro, North Carolina, United States of America.
authors: Anthony L
authors: AL
authors: Dellinger
authors: 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.
authors: Pierre
authors: P
authors: Cunin
authors: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: David
authors: D
authors: Lee
authors: Dana Farber Institute, Boston, Massachusetts, United States of America.
authors: Andrew L
authors: AL
authors: Kung
authors: Luna Innovations Incorporated, Danville, Virginia, United States of America.
authors: D Bradford
authors: DB
authors: Brooks
authors: Luna Innovations Incorporated, Danville, Virginia, United States of America.
authors: Zhiguo
authors: Z
authors: Zhou
authors: 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.
authors: Peter A
authors: PA
authors: Nigrovic
authors: University of North Carolina Greensboro, Joint School of Nanosceince and Nanoengineering, Greensboro, North Carolina, United States of America.
authors: Christopher L
authors: CL
authors: Kepley
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015153:Blotting, Western; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D037741:Fullerenes / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000378:metabolism; D049329:Nanostructures / Q000008:administration & dosage*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D037741:Fullerenes; D016328:NF-kappa B; D017382:Reactive Oxygen Species