title: Alleviation of rheumatoid arthritis by cell-transducible methotrexate upon transcutaneous delivery.
abstract: Rheumatoid arthritis (RA) is a systemic autoimmune disease that is initiated and maintained by various inflammatory/immune cells and their cytokines, leading to cartilage degradation and bone erosion. Despite its potent therapeutic efficacy on RA, the oral administration of methotrexate (MTX) provokes serious adverse systemic complications, thus necessitating the local application of MTX. Here, we show that transcutaneous MTX (TC-MTX) can efficiently penetrate joint skin ex vivo and in vivo, and that TC-MTX can significantly improve the various inflammatory symptoms associated with RA. Further, TC-MTX preserved the joint-structures in mice with collagen-induced arthritis (CIA), which was also confirmed by three-dimensional micro-computed tomography scan. TC-MTX markedly decreased the secretion of inflammatory cytokines both in the serum and in inflamed joints of CIA mice. Further, its therapeutic potential is comparable to that of etanercept, a biological agent that block tumor necrosis factor (TNF)-α. Importantly, the systemic cytotoxicity of TC-MTX was not detected. Thus, TC-MTX can be a new therapeutic modality for RA patients without systemic complications.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Kim
authors.forename: Min-Chan
authors.initials: MC
authors.lastname: Park
authors.forename: Yong-Beom
authors.initials: YB
authors.lastname: Park
authors.forename: Wook Jin
authors.initials: WJ
authors.lastname: Chae
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.forename: Dong-Ho
authors.initials: DH
authors.lastname: Lee
authors.forename: Sang-Hwa
authors.initials: SH
authors.lastname: Yang
authors.forename: Seung-Kyou
authors.initials: SK
authors.lastname: Lee
authors.forename: Soo-Kon
authors.initials: SK
authors.lastname: Lee
authors.forename: Sang-Kyou
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D000068800:Etanercept; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D016896:Treatment Outcome; D055114:X-Ray Microtomography
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D018124:Receptors, Tumor Necrosis Factor; D013762:Tetrahydrofolate Dehydrogenase; D000068800:Etanercept; D008727:Methotrexate